Search

Abstract Background Subsequent short‐latency leukemias are well‐described among survivors of childhood cancer. However, late (5–14.9 years from diagnosis, LL) and very late (≥15 years from diagnosis, VLL) subsequent leukemias have not been well studied. We assessed risk factors, prevalence, and outcomes for LL and VLL in the Childhood Cancer Survivor Study cohort. Methods Subsequent leukemias, among 25,656 five‐year survivors, were self‐reported and confirmed by pathology review. Standardized incidence ratios (SIR) and cumulative incidences were calculated, and relative risks (RR) were estimated using Cox regression for exposures. Results Seventy‐seven survivors developed subsequent leukemia, 49 survivors with LL (median time from diagnosis 7.8 years, range 5.0–14.5 years) and 28 with VLL (median time from diagnosis 25.4 years, range 15.9–42.8 years), with a cumulative incidence of 0.23% (95% CI 0.18%–0.30%) 20 years from diagnosis for all subsequent leukemias. The most common leukemia subtypes were acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia. Compared to the general population, survivors were at increased risk, for developing LL (SIR 9.3, 95% CI 7.0–12.1) and VLL (SIR 5.9, 95% CI 3.9–8.4). In multivariable relative risk analyses, cumulative epipodophyllotoxin dose >4000 mg/m2 was associated with increased risk for LL and VLL (RR 4.5, 95% CI 2.0–9.9). Conclusions In this large series of late subsequent leukemias, survivors of childhood cancer are at increased risk, with no evidence of plateau over time. We observed most risk among survivors who received high cumulative doses of epipodophyllotoxins. Ongoing consideration for this late effect should continue beyond 10 years.

Abstract Background Survivors of childhood central nervous system (CNS) tumors can develop motor and sensory impairment from their cancer and treatment history. We estimated the prevalence of motor and sensory impairment in survivors compared with controls through clinical assessment and identified associated treatment exposures and functional, quality of life (QOL), and social outcomes. Methods Survivors of childhood CNS tumors from the St. Jude Lifetime Cohort (n = 378, median [range] age 24.0 [18.0–53.0] years, 43.4% female) ≥5 years from diagnosis and controls (n = 445, median [range] age 34.0 [18.0–70.0] years, 55.7% female) completed in‐person evaluation for motor and sensory impairment using the modified Total Neuropathy Score. Impairment was graded by modified Common Terminology Criteria for Adverse Events. Multivariable models estimated associations between grade ≥2 motor/sensory impairment, individual/treatment characteristics, and secondary outcomes (function by Physical Performance Test, fitness by physiologic cost index, QOL by Medical Outcomes Survey Short Form‐36 physical/mental summary scores, social attainment). Results Grade ≥2 motor or sensory impairment was more prevalent in survivors (24.1%, 95% Confidence Interval [CI] 19.8%–29.4%) than controls (2.9%, CI 1.4–4.5%). Among survivors, in multivariable models, motor impairment was associated with vinca exposure 2036 mg/m2 versus none (OR 12.61, CI 2.19–72.72). Sensory impairment was associated with older age at diagnosis (OR 1.09, CI 1.01–1.16) and craniospinal irradiation versus none (OR 4.39, CI 1.68–11.50). There were lower odds of motor/sensory impairment in survivors treated in the year 2000 or later versus before 1990 (Motor: OR 0.29, CI 0.10–0.84, Sensory: OR 0.35, CI 0.13–0.96). Motor impairment was associated with impaired physical QOL (OR 2.64, CI 1.22–5.72). Conclusions In survivors of childhood CNS tumors, motor and sensory impairment is prevalent by clinical assessment, especially after exposure to etoposide, vinca, or craniospinal radiation. Treating motor impairment may improve survivors' QOL.

Patients with relapsed/refractory (R/R) transformed diffuse large B-cell lymphoma (DLBCL) from indolent B-cell lymphomas, including Richter transformation (RT), have a poor prognosis. PD-1/PD-L1 antibodies produce modest objective and complete response rates (ORR and CRR) in B-NHL as monotherapy but may synergize with immunogenic chemotherapies like gemcitabine and oxaliplatin (GemOx). Thus, we evaluated the safety and efficacy of atezolizumab plus rituximab and GemOx (R-GemOx+Atezo) in R/R transformed DLBCL, including RT. We conducted a phase I trial including patients with transformed DLBCL after ≥1 prior therapy. Patients received up to 4 cycles of R-GemOx-+Atezo. Patients in CR could then proceed to Ratezo maintenance until progression. A safety lead-in with dose-limiting toxicity (DLT) evaluation was enrolled to confirm the recommended phase 2 dose (RP2D), followed by 2 expansion cohorts: one for transformed follicular lymphoma (FL) and another for non-FL transformed DLBCL, including RT. Twenty-seven patients were enrolled. One of the 6 safety lead-in patients had a DLT attributed to atezolizumab, a grade 4 Stevens-Johnson syndrome (SJS). The most common grade ≥3 events were neutropenia (18.5%), lymphopenia (18.5%), and thrombocytopenia (14.8%). The overall and complete response rates (ORR and CRR) were 59% and 33%, respectively. The ORR and CRR in transformed FL were 79% and 43%, and 38% and 23% in transformed non-FL, respectively. The median PFS and OS of the total population were 4.2 and 7.7 months, respectively. R-GemOx+Atezo was well tolerated and demonstrated promising preliminary efficacy in patients with R/R transformed DLBCL.

Abstract Objective To examine associations between neurologic late effects and attainment of independence in adult survivors of childhood cancer treated with central nervous system (CNS)‐directed therapies. Methods A total of 7881 survivors treated with cranial radiation therapy (n = 4051; CRT) and/or intrathecal methotrexate (n = 4193; IT MTX) ([CNS‐treated]; median age [range] = 25.5 years [18–48]; time since diagnosis = 17.7 years [6.8–30.2]) and 8039 without CNS‐directed therapy reported neurologic conditions including stroke, seizure, neurosensory deficits, focal neurologic dysfunction, and migraines/severe headaches. Functional independence was assessed using latent class analysis with multiple indicators (independent living, assistance with routine and personal care needs, ability to work/attend school, attainment of driver's license, marital/partner status). Multivariable regression models, adjusted for age, sex, race/ethnicity, and chronic health conditions, estimated odds ratios (OR) or relative risks (RR) for associations between neurologic morbidity, functional independence, and emotional distress. Results Among CNS‐treated survivors, three classes of independence were identified: (1) moderately independent, never married, and non‐independent living (78.7%); (2) moderately independent, unable to drive (15.6%); and (3) non‐independent (5.7%). In contrast to 50% of non‐CNS‐treated survivors and 60% of siblings, a fourth fully independent class of CNS‐treated survivors was not identified. History of stroke (OR = 2.50, 95% CI: 1.70–3.68), seizure (OR = 9.70, 95% CI: 7.37–12.8), neurosensory deficits (OR = 2.67, 95% CI: 2.16–3.31), and focal neurologic dysfunction (OR = 3.05, 95% CI: 2.40–3.88) were associated with non‐independence among CNS‐treated survivors. Non‐independence was associated with emotional distress symptoms. Interpretation CNS‐treated survivors do not attain full independence comparable to non‐CNS‐treated survivors or siblings. Interventions to promote independence may be beneficial for survivors with treatment‐related neurological sequalae.

The potato leafhopper (Empoasca fabae, PLH) is a serious pest that feeds on a wide range of agricultural crops and is found throughout the United States but is not known to be a vector for plant-infecting viruses. We probed the diversity of virus sequences in field populations of PLH collected from four Midwestern states: Illinois, Indiana, Iowa, and Minnesota. High-throughput sequencing data from total RNAs extracted from PLH were used to assemble sequences of fifteen positive-stranded RNA viruses, two negative-stranded RNA viruses, and one DNA virus. These sequences included ten previously described plant viruses and eight putative insect-infecting viruses. All but one of the insect-specific viruses were novel and included three solemoviruses, one iflavirus, one phenuivirus, one lispivirus, and one ambidensovirus. Detailed analyses of the novel genome sequences and their evolutionary relationships with related family members were conducted. Our study revealed a diverse group of plant viruses circulating in the PLH population and discovered novel insect viruses, expanding knowledge on the untapped virus diversity in economically important crop pests. Our findings also highlight the importance of monitoring the emergence and circulation of plant-infecting viruses in agriculturally important arthropod pests.

Abstract Background Whether diet has beneficial effects on cardiovascular disease (CVD) in childhood cancer survivors as in the general population is unknown. Therefore, we examined associations between dietary patterns and risk of CVD in adult survivors of childhood cancer. Methods Childhood cancer survivors, 18–65 years old in the St Jude Lifetime Cohort (1882 men and 1634 women) were included in the analysis. Dietary patterns were defined by the adherence to the Healthy Eating Index (HEI)–2015, Dietary Approaches to Stop Hypertension (DASH), and alternate Mediterranean diet (aMED) based on a food frequency questionnaire at study entry. CVD cases (323 in men and 213 in women) were defined as participants with at least one grade 2 or higher CVD-related diagnosis at baseline. Multivariable logistic regression adjusted for confounders was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of CVD. Results Greater adherence to HEI-2015 (OR=0.88, 95% CI: 0.75–1.03, per 10 score increment), DASH (OR=0.85, 95% CI: 0.71–1.01, per 10 score increment), and aMED (OR=0.92, 95% CI: 0.84–1.00, each score increment) were, albeit trending towards significance, associated with a lower risk of CVD in women. HEI-2015 was associated with a non-significantly lower risk of CVD in men (ORQ5 vs. Q1=0.80, 95% CI: 0.50–1.28). These dietary patterns were also associated with a lower risk of CVD in survivors with high underlying CVD risk. Conclusions As recommended to the general population, a diet rich in plant foods and moderate in animal foods needs to be a part of CVD management and prevention in childhood cancer survivors.

AbstractResearch from several high-income countries links early menarche with an increased risk for sexual violence. However, the role of early menarche in adolescent girls’ and young women’s sexual violence risk in sub-Saharan Africa, where sexual violence rates are high, is not well understood. The current study explores the association between early menarche and sexual violence in Ghana with secondary analysis of data collected from 700 adolescent girls and young women followed over three years. Logistic regressions were used to assess the cross-sectional association between early menarche and sexual violence. Generalised estimating equations were used to assess whether the association between early menarche and sexual violence persisted over time. Inverse odds weighting was used to test potential mediators of the association between early menarche and sexual violence. Sexual violence was fairly common in the study sample, with 27% reporting having experienced sexual violence at baseline, and approximately 50% at year three. Early menarche was associated with 72% greater odds of having experienced sexual violence at baseline (95% confidence interval: 1.01–2.93). However, the odds ratio attenuated and lost significance over the three-year study period, with a lower risk of sexual violence among girls with early menarche at year three. Neither child marriage nor early sexual initiation significantly mediated the association between early menarche and sexual violence. The findings suggest that early-maturing girls may be particularly vulnerable to sexual violence in early adolescence, thus necessitating prevention interventions around the time of menarche to reduce the risk for sexual violence.

Abstract Background Understanding the relationship between adolescent pregnancy and adult education and employment outcomes is complicated due to the endogeneity of fertility behaviors and socio-economic functioning. Studies exploring adolescent pregnancy have often relied on limited data to measure adolescent pregnancy (i.e. birth during adolescence or self-reports) and lack access to objective measures of school performance during childhood. Methods We use rich administrative data from Manitoba, Canada, to assess women’s functioning during childhood (including pre-pregnancy academic performance), fertility behaviors during adolescence (live birth, abortion, pregnancy loss, or no history of pregnancy), and adult outcomes of high school completion and receipt of income assistance. This rich set of covariates allows calculating propensity score weights to help adjust for characteristics possibly predictive of adolescent pregnancy. We also explore which risk factors are associated with the study outcomes. Results We assessed a cohort of 65,732 women, of whom 93.5% had no teen pregnancy, 3.8% had a live birth, 2.6% had abortion, and

Abstract Ground ivy (Glechoma hederacea L.) is a perennial broadleaf weed in the mint family (Lamiaceae) that is commonly found in turf in the temperate climates of the United States. Cultural practices that maintain dense turf are the best way to reduce weeds; however, cultural control methods alone cannot provide complete weed control. Herbicides are commonly used to control weeds in the turfgrass industry, but interest in alternative control methods is increasing. Applications of iron‐based products are an alternative chemical weed control option in turfgrass systems, but other micronutrients, such as boron, may also be a viable option. The objective of this study was to compare the efficacy of a chelated iron product as well as different boron‐based products for ground ivy control and also determine if these products injure Kentucky bluegrass (Poa pratensis L.). The products evaluated included borax, boric acid, Solubor (disodium octaborate tetrahydrate), and Fiesta (FeHEDTA) with a low and high rate tested for each. Ground ivy cover was reduced 77% or more from a single October application of all boron sources at the high rates and the high rate of Fiesta when evaluated 9 months later. The high rate of all boron‐containing products caused unacceptable turfgrass injury (

Abstract Rising salinity from road deicing salts threatens the survival and reproduction of freshwater organisms. We conducted two experiments to address how Daphnia pulex survival and reproduction were affected by road salt concentration (control, 120, 640 and 1200 mg Cl−/L) crossed with three concentrations of water hardness (20, 97, 185 mg CaCO3 /L). D. pulex survival was poor in our hard water treatment in both experiments (185 mg CaCO3 /L), potentially indicating a low tolerance to hard water for the strain used in our experiments. With the remaining two hardness treatments (20 and 97 mg CaCO3 /L), we found no evidence of an interactive effect between salt concentration and water hardness on D. pulex survival. In our population-level experiment, D. pulex survival was reduced by > 60% at 120 mg Cl−/L compared to the control. In the individual experiment, survival was similar between the control and 120 mg Cl−/L, but ≤ 40% of individuals survived in 640 and 1200 mg Cl−/L. For the surviving individuals across all treatments, the number of offspring produced per individual declined with increasing Cl− concentration and in hard water. Our results indicate that current Cl− thresholds may not protect some zooplankton and reduced food availability per capita may enhance the negative impacts of road salt.

Abstract Background DNA methylation (DNAm) plays an important role in lipid metabolism, however, no epigenome-wide association study (EWAS) of lipid levels has been conducted among childhood cancer survivors. Here, we performed EWAS analysis with longitudinally collected blood lipid data from survivors in the St. Jude lifetime cohort study. Methods Among 2052 childhood cancer survivors of European ancestry (EA) and 370 survivors of African ancestry (AA), four types of blood lipids, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG), were measured during follow-up beyond 5-years from childhood cancer diagnosis. For the exposure EWAS (i.e., lipids measured before blood draw for DNAm), the DNAm level was an outcome variable and each of the blood lipid level was an exposure variable; vice versa for the outcome EWAS (i.e., lipids measured after blood draw for DNAm). Results Among EA survivors, we identified 43 lipid-associated CpGs in the HDL (n = 7), TC (n = 3), and TG (n = 33) exposure EWAS, and 106 lipid-associated CpGs in the HDL (n = 5), LDL (n = 3), TC (n = 4), and TG (n = 94) outcome EWAS. Among AA survivors, we identified 15 lipid-associated CpGs in TG exposure (n = 6), HDL (n = 1), LDL (n = 1), TG (n = 5) and TC (n = 2) outcome EWAS with epigenome-wide significance (P 70%) between EA and AA survivors, highlighting differences in DNAm markers of blood lipids between populations with diverse genetic ancestry. Ten lipid-associated CpGs were cis-expression quantitative trait methylation with their DNAm levels associated with the expression of corresponding genes, out of which seven were negatively associated. Conclusions We identified distinct signatures of DNAm for blood lipids as exposures or outcomes and between EA and AA survivors, revealing additional genes involved in lipid metabolism and potential novel targets for controlling blood lipids in childhood cancer survivors.

Abstract Background Survivors of childhood cancer are at risk for therapy-related dental diseases. The purpose of the study was to investigate the associations between clinical, socioeconomic, and demographic factors and oral diseases in the St. Jude Lifetime Cohort (SJLIFE) participants. Methods We performed a retrospective medical chart review and evaluated longitudinal self-reported dental outcomes in 4856 childhood cancer survivors and 591 community controls participating in the St. Jude Lifetime Cohort (SJLIFE) study. Univariate and multivariable logistic regression models were used to assess the impact of socioeconomic factors, treatment exposures and patient demographics on dental outcomes. Results Cancer survivors were more likely to report microdontia (odds ratio (OR) = 7.89, 95% confidence interval (CI) [4.64, 14.90]), abnormal root development (OR = 6.19, CI [3.38, 13.00]), hypodontia (OR = 2.75, CI [1.83, 4.33]), enamel hypoplasia (OR = 4.24, CI [2.9, 6.49]), xerostomia (OR = 7.72, CI [3.27, 25.10]), severe gingivitis (OR = 2.04, CI [1.43, 3.03]), and ≥ 6 missing teeth (OR = 3.73, CI [2.46, 6.00]) compared to controls without cancer history. Survivors who received classic alkylating agents (OR = 1.6, CI [1.36, 1.88]), anthracycline antibiotics (OR = 1.22, CI [1.04, 1.42] or radiation therapy potentially exposing the oral cavity (OR = 1.48, CI [1.26, 1.72]) were more likely to report at least one dental health problem after controlling for socioeconomic factors, age at last follow-up and diagnosis, other treatment exposures, and access to dental services. Survivors who had radiation therapy potentially exposing the oral cavity (OR = 1.52, CI [1.25, 1.84]) were also more likely to report at least one soft tissue abnormality after controlling for socioeconomic factors, age at last follow-up and diagnosis, other treatment exposures, and access and utilization of dental services. Conclusions Childhood cancer survivors have a higher prevalence of oral-dental abnormalities than the controls without a cancer history. Cancer treatment, socioeconomic factors, and access to oral health care contribute to the prevalence of dental abnormalities.

Social epigenomics is an emerging field in which social scientist collaborate with computational biologists, especially epigeneticists, to address the underlying pathway for biological embedding of life experiences. This social epigenomics study included long-term childhood cancer survivors enrolled in the St. Jude Lifetime Cohort. DNA methylation (DNAm) data were generated using the Illumina EPIC BeadChip, and three social determinants of health (SDOH) factors were assessed: self-reported educational attainment, personal income, and an area deprivation index based on census track data. An epigenome-wide association study (EWAS) was performed to evaluate the relation between DNAm at each 5’-cytosine-phosphate-guanine-3’ (CpG) site and each SDOH factor based on multivariable linear regression models stratified by ancestry (European ancestry, n = 1,618; African ancestry, n = 258). EWAS among survivors of European ancestry identified 130 epigenome-wide significant SDOH–CpG associations (P

Outcomes after programmed death-1 (PD-1) blockade in B-cell lymphomas are disappointing with few durable responses. Histone deacetylase inhibitors exhibit favorable immunomodulatory effects and demonstrate synergistic anti-tumor immune responses with anti-PD-1 therapy in preclinical models. We, therefore, developed a phase I study to evaluate the safety and preliminary efficacy of pembrolizumab with vorinostat in relapsed/refractory B-cell lymphomas. Patients were treated in a dose-escalation cohort using a Rolling 6 design followed by an expansion cohort at the recommended phase II dose (R2PD). Fifty-two patients were enrolled (32 Hodgkin and 20 non-Hodgkin lymphoma [NHL]). Here, we report safety data from the dose escalation cohort, and the toxicity and efficacy within NHL patients. Vorinostat was administered twice daily on days 1-5 and 8-12 (dose-level [DL]1: 100 mg; DL2: 200 mg) and pembrolizumab (200 mg) was administered on day 1 of each 3-week cycle. Of six patients treated at DL1, one had a dose-limiting toxicity (DLT) (Stevens-Johnson syndrome [SJS]), and one of six had a DLT at DL2 (thromboembolism); therefore, DL2 was the RP2D. The patient developing SJS was treated with corticosteroids, infliximab, and cyclosporine but ultimately died of invasive fungal infection from the extensive immunosuppression used to treat the SJS. The most common adverse events were hypertension, diarrhea, and cytopenias. Of 20 NHL patients, nine had follicular lymphoma (FL) and 11 had diffuse large B-cell lymphoma (DLBCL). Five DLBCL patients had primary mediastinal B-cell lymphoma (PMBL). The complete and overall response rates (CR and ORR) were 11% and 22% for FL and 45% and 55% for all DLBCL. Amongst DLBCL, the CR and ORR was 80% and 80% for PMBL and 17% and 33% for non-PMBL. In conclusion, pembrolizumab with vorinostat was tolerable and produced responses in relapsed/refractory B-cell NHL, with particularly notable efficacy in PMBL (clinicaltrials gov. Identifier: NCT03150329).

IMPORTANCE:. Which social factors explain racial and ethnic disparities in COVID-19 access to care and outcomes remain unclear. OBJECTIVES:. We hypothesized that preferred language mediates the association between race, ethnicity and delays to care. DESIGN, SETTING AND PARTICIPANTS:. Multicenter, retrospective cohort study of adults with COVID-19 consecutively admitted to the ICU in three Massachusetts hospitals in 2020. MAIN OUTCOME AND MEASURES:. Causal mediation analysis was performed to evaluate potential mediators including preferred language, insurance status, and neighborhood characteristics. RESULTS:. Non-Hispanic White (NHW) patients (157/442, 36%) were more likely to speak English as their preferred language (78% vs. 13%), were less likely to be un- or under-insured (1% vs. 28%), lived in neighborhoods with lower social vulnerability index (SVI) than patients from racial and ethnic minority groups (SVI percentile 59 [28] vs. 74 [21]) but had more comorbidities (Charlson comorbidity index 4.6 [2.5] vs. 3.0 [2.5]), and were older (70 [13.2] vs. 58 [15.1] years). From symptom onset, NHW patients were admitted 1.67 [0.71–2.63] days earlier than patients from racial and ethnic minority groups (p < 0.01). Non-English preferred language was associated with delay to admission of 1.29 [0.40–2.18] days (p < 0.01). Preferred language mediated 63% of the total effect (p = 0.02) between race, ethnicity and days from symptom onset to hospital admission. Insurance status, social vulnerability, and distance to the hospital were not on the causal pathway between race, ethnicity and delay to admission. CONCLUSIONS AND RELEVANCE:. Preferred language mediates the association between race, ethnicity and delays to presentation for critically ill patients with COVID-19, although our results are limited by possible collider stratification bias. Effective COVID-19 treatments require early diagnosis, and delays are associated with increased mortality. Further research on the role preferred language plays in racial and ethnic disparities may identify effective solutions for equitable care.

Abstract Genetic influence shapes who develops posttraumatic stress disorder (PTSD) after traumatic events. However, the genetic variants identified for PTSD may in fact be associated with traumatic exposures (e.g., interpersonal violence), which appear heritable as well. Childhood cancer survivors (CCS) are at risk for PTSD, but genetic influences affecting cancer are unlikely to overlap with those affecting PTSD. This offers a unique opportunity to identify variants specific to PTSD risk. In a genome-wide association study (GWAS), 3984 5-year survivors of childhood cancer of European-ancestry from the Childhood Cancer Survivor Study (CCSS) were evaluated for discovery and 1467 survivors from the St. Jude Lifetime (SJLIFE) cohort for replication. Childhood cancer-related PTSD symptoms were assessed using the Posttraumatic Stress Diagnostic Scale in CCSS. GWAS was performed in CCSS using logistic regression and lead markers were replicated/meta-analyzed using SJLIFE. Cross-associations of identified loci were examined between CCS and the general population. PTSD criteria were met for 671 participants in CCSS and 161 in SJLIFE. Locus 10q26.3 was significantly associated with PTSD (rs34713356, functionally mapped to ECHS1, P = 1.36 × 10–8, OR 1.57), and was replicated in SJLIFE (P = 0.047, OR 1.37). Variants in locus 6q24.3-q25.1 reached marginal significance (rs9390543, SASH1, P = 3.56 × 10–6, OR 0.75) in CCSS and significance when meta-analyzing with SJLIFE (P = 2.02 × 10–8, OR 0.75). Both loci were exclusively associated with PTSD in CCS rather than PTSD/stress-related disorders in general population (P-for-heterogeneity

Summary: Background: Childhood cancer survivors are at elevated risk for poor health-related quality-of-life (HRQOL). Identification of potentially modifiable risk factors associated with HRQOL is needed to inform survivorship care. Methods: Participants included 4294 adult childhood cancer survivors from the St. Jude Lifetime Cohort Study who completed a survey and clinical assessment at entry into the survivorship cohort (baseline) and follow-up (median interval: 4.3 years) between 2007 and 2019. The SF-6D compared utility-based HRQOL of survivors to an independent sample from the U.S. Medical Expenditures Panel Survey. Chronic health conditions (CHCs) were graded using modified Common Terminology Criteria for Adverse Events. General linear models examined cross-sectional and temporal associations of HRQOL with CHC burden (total and by organ-system), adjusting for potential risk factors. Findings: Survivors reported poorer HRQOL compared to the general population (effect size [d] = −0.343). In cross-sectional analyses at baseline, significant non-demographic risk factors included higher total CHC burden (driven by more severe cardiovascular [d = −0.119, p = 0.002], endocrine [d = −0.112, p = 0.001], gastrointestinal [d = −0.226, p

Abstract Background Increased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA. Methods Genome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against the allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability. Results For EAA-Horvath, a genome-wide significant association was mapped to the SELP gene with the strongest SNP rs732314 (meta-GWAS: β=0.57, P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed a substantial heterogeneity between children and adults (meta-GWAS: β=0.97 vs. 0.51, I 2 =73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31, I 2 =66.3%). For EAA-Hannum, an association was mapped to the HLA locus with the strongest SNP rs28366133 (meta-GWAS: β=0.78, P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09, P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21, P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge. Conclusions We identified novel genetic variants in the SELP gene and HLA region associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate the identification of survivors at higher risk in developing accelerated aging and potentially inform drug targets for future intervention strategies among vulnerable survivors.

Abstract Background Previous research has established that exposure to high maternal sensitivity is positively associated with advances in infant cognitive development. However, there are many fixed and modifiable factors that influence this association. This study investigates whether the association between maternal sensitivity and infant cognitive development in the first year of life is accounted for by other factors, such as breastfeeding, maternal depressive symptoms, maternal alcohol use, infant birth weight or demographic covariates. Methods Using data from the Early Childhood Longitudinal Study-Birth (ECLS-B) Cohort, a nationally representative sample of U.S. born children, multi-variable regression analyses was used to examine whether breastfeeding, maternal depressive symptoms and alcohol use were associated with maternal sensitivity, as measured by the Nursing Child Assessment Teaching Scale (NCATS), and with infant cognitive development, as measured by the Bayley Scales of Infant Development, Short Form, Research Edition, after controlling for demographic covariates (infant sex, maternal age, education, race/ethnicity, income, parity, family structure) and infant birth weight. Results Breastfeeding, depressive symptoms and alcohol use were not associated with maternal sensitivity scores after controlling for demographic covariates and infant birth weight. However, breastfeeding (β = .079, p

BackgroundProsocial behavior has positive social, cognitive, and physical health effects on the individual exhibiting the behavior as well as on society as a whole, and is integral to overall mental and physical wellbeing. The development of prosocial behavior is rooted in early childhood and learned through observation. As such, those spending time with children, especially their caregiver, play a critical role in their prosocial development. The current study investigates the impact of caregiver mental health on the prosocial development of young children over time.MethodsThis paper presents a secondary analysis of child prosocial development in the Asenze Study, a longitudinal, population-based cohort study based in KwaZulu-Natal, South Africa. Children were followed-up over time from an average age of five to seven years along with their caregivers. Linear GEE regression analysis was used to assess whether a change in presence of a mental health disorder in a caregiver during this 2-year interval (using the Client Diagnostic Questionnaire) impacted the development of their child's prosocial behavior (using the Strengths and Difficulties Questionnaire).ResultsAfter adjusting for early child-care, child HIV status, SDQ child prosocial subscale, SDQ total difficulties score, and household order score (CHAOS), children whose caregivers acquired a mental health disorder had a significantly smaller increase in prosocial behavioral development compared to children whose caregivers never had a mental health disorder.ConclusionsIdentifying contextually relevant modifiable factors such as this will help stimulate the development of interventions to promote prosocial development in childhood.

Background It is well established that maternal mental illness is associated with an increased risk of poor development for children. However, inconsistencies in findings regarding the nature of the difficulties children experience may be explained by methodological or geographical differences. Aims We used a common methodological approach to compare developmental vulnerability for children whose mothers did and did not have a psychiatric hospital admission between conception and school entry in Manitoba, Canada, and Western Australia, Australia. We aimed to determine if there are common patterns to the type and timing of developmental difficulties across the two settings. Method Participants included children who were assessed with the Early Development Instrument in Manitoba, Canada (n = 69 785), and Western Australia, Australia (n = 19 529). We examined any maternal psychiatric hospital admission (obtained from administrative data) between conception and child's school entry, as well as at specific time points (pregnancy and each year until school entry). Results Log-binomial regressions modelled the risk of children of mothers with psychiatric hospital admissions being developmentally vulnerable. In both Manitoba and Western Australia, an increased risk of developmental vulnerability on all domains was found. Children had an increased risk of developmental vulnerability regardless of their age at the time their mother was admitted to hospital. Conclusions This cross-national comparison provides further evidence of an increased risk of developmental vulnerability for children whose mothers experience severe mental health difficulties. Provision of preventative services during early childhood to children whose mothers experience mental ill health may help to mitigate developmental difficulties at school entry.

The use of publicly available sequencing datasets as controls (hereafter, "public controls") in studies of rare variant disease associations has great promise but can increase the risk of false-positive discovery. The specific factors that could contribute to inflated distribution of test statistics have not been systematically examined. Here, we leveraged both public controls, gnomAD v2.1 and several datasets sequenced in our laboratory to systematically investigate factors that could contribute to the false-positive discovery, as measured by λΔ95, a measure to quantify the degree of inflation in statistical significance. Analyses of datasets in this investigation found that 1) the significantly inflated distribution of test statistics decreased substantially when the same variant caller and filtering pipelines were employed, 2) differences in library prep kits and sequencers did not affect the false-positive discovery rate and, 3) joint vs. separate variant-calling of cases and controls did not contribute to the inflation of test statistics. Currently available methods do not adequately adjust for the high false-positive discovery. These results, especially if replicated, emphasize the risks of using public controls for rare-variant association tests in which individual-level data and the computational pipeline are not readily accessible, which prevents the use of the same variant-calling and filtering pipelines on both cases and controls. A plausible solution exists with the emergence of cloud-based computing, which can make it possible to bring containerized analytical pipelines to the data (rather than the data to the pipeline) and could avert or minimize these issues. It is suggested that future reports account for this issue and provide this as a limitation in reporting new findings based on studies that cannot practically analyze all data on a single pipeline.

Experts in symptomatic generalized joint hypermobility (S-GJH) agree that upper cervical instability (UCI) needs to be better recognized in S-GJH, which commonly presents in the clinic as generalized hypermobility spectrum disorder and hypermobile Ehlers-Danlos syndrome. While mild UCI may be common, it can still be impactful; though considerably less common, severe UCI can potentially be debilitating. UCI includes both atlanto-occipital and atlantoaxial instability. In the absence of research or published literature describing validated tests or prediction rules, it is not clear what signs and symptoms are most important for diagnosis of UCI. Similarly, healthcare providers lack agreed-upon ways to screen and classify different types or severity of UCI and how to manage UCI in this population. Consequently, recognition and management of UCI in this population has likely been inconsistent and not based on the knowledge and skills of the most experienced clinicians. The current work represents efforts of an international team of physical/physiotherapy clinicians and a S-GJH expert rheumatologist to develop expert consensus recommendations for screening, assessing, and managing patients with UCI associated with S-GJH. Hopefully these recommendations can improve overall recognition and care for this population by combining expertise from physical/physiotherapy clinicians and researchers spanning three continents. These recommendations may also stimulate more research into recognition and conservative care for this complex condition.

Seaside petunia (Calibrachoa parviflora) is a mat-forming plant species that was recently reported in fall-seeded onion (Allium cepa) in the southwestern United States. To initiate development of herbicide recommendations for seaside petunia in onion, we conducted a study to determine seaside petunia susceptibility to commonly used herbicides for broadleaf weed control after onion emergence. Our study included herbicides applied at below-label rates, which provided insights on seaside petunia responses to reductions in the amount of herbicide available for plant absorption. For herbicides with preemergence activity, our growth chamber study indicated that soil applications of flumioxazin or oxyfluorfen (0.06 and 0.25 lb/acre, respectively) prevented seaside petunia seedling emergence when applied at 0.125×, 0.25×, 0.5×, and 1.0× the labeled rates for onion. Labeled rate treatments of dimethenamid-P (0.84 lb/acre) and S-metolachlor (0.64 lb/acre) inhibited seedling emergence similar to labeled rate treatments of flumioxazin and oxyfluorfen; however, below-label rate treatments of dimethenamid-P and S-metolachlor resulted in diminished control of seaside petunia compared with the labeled rate treatments. Following labeled rate applications of dimethyl tetrachloroterephthalate [DCPA (6 lb/acre)] and pendimethalin (0.71 lb/acre), more than 50% of seaside petunia seedlings emerged compared with the nontreated control. For herbicides with postemergence activity on weeds, our greenhouse study indicated that bromoxynil at 0.37 lb/acre, flumioxazin at 0.06 lb/acre, and oxyfluorfen at 0.25 lb/acre equally reduced growth of seaside petunia plants that were small at the time of spraying (stem length, 1–2 cm). Postemergence control of seaside petunia with oxyfluorfen and flumioxazin decreased as plant size at spraying increased; however, bromoxynil effects on seaside petunia remained high as stem length at spraying increased from 5 to 12 cm. Based on the results of this study, we conclude that promising herbicide programs for seaside petunia in onion include oxyfluorfen or flumioxazin for preemergence control and bromoxynil for postemergence control. These herbicides, alone and in combination, should be evaluated for seaside petunia control and onion phytotoxicity in future field trials.

BackgroundOver 50% of childhood cancer survivors are exercise intolerant, with maximal aerobic capacities comparable to individuals decades older, suggesting early physiologic ageing. In addition, 36% of survivors are obese. Optimal exercise capacity provides a foundation to support daily function and healthy body habitus and is associated with benefits to cognition, cardiovascular health, and longevity. Cellular senescence and inflammation are key mechanisms that drive age-related disease, quantifiable as biomarkers in peripheral blood.AimsThis study aimed to evaluate associations between p16INKa, a biomarker of cellular senescence, and inflammation and exercise capacity among adult survivors of childhood cancer.Materials and methodsEligible survivors were recruited from the St. Jude Lifetime (SJLIFE) Cohort Study. Exercise capacity was assessed by maximal oxygen uptake (VO2, ml/kg/min) obtained via cardiopulmonary exercise testing using a modified Bruce protocol. Body fat (%) was determined from dual energy x-ray absorptiometry (DEXA). Peripheral blood samples were used to evaluate log2 p16INK4a mRNA expression, a biomarker of cellular senescence, and inflammation with high sensitivity C-reactive protein (hs-CRP) levels. Multivariable regression evaluated associations between p16INK4a, hs-CRP, body fat, and exercise capacity.ResultsParticipants included 185 five-year childhood cancer survivors (mean age 36.6 [range 20.1 - 55.7] years, 44% male, 77% non-Hispanic white, 53% leukemia/lymphoma). Compared to males, females had lower peak VO2 (mean ± SD, 22.5 ± 8.2 vs. 28.8 ± 7.7 ml/kg/min, p

Purpose The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer was established in 2018 to address gaps in knowledge of risk and risk factors for breast cancer subsequent to childhood/adolescent cancer by pooling individual patient data from seven cohorts. Initially, the pooled cohort will focus on three clinically relevant questions regarding treatment-related subsequent breast cancer risk in female survivors, which are the risk related to low-dose radiotherapy exposure to the chest, specific chemotherapy agents and attained age.Participants The consortium database includes pooled data on 21 892 female survivors from seven cohorts in North America and Europe with a primary cancer diagnosis at

PurposeAdult survivors of childhood acute lymphoblastic leukemia (ALL) have impaired adaptive physical function and poor health-related quality of life (HRQoL). Obesity may contribute to these impairments by increasing the physiological cost of walking. Due to treatment exposures during ALL therapy, survivors’ cost of walking may be more impacted by obesity than the general population. Therefore, we examined associations between obesity, persistent motor neuropathy, and energy cost of walking; and examined associations between energy cost of walking, adaptive physical function, and HRQoL, in adult survivors of childhood ALL vs. community controls.MethodsObesity was measured via body mass index (BMI) and body fat percentage. The physiological cost index (PCI) was calculated from the six-minute walk test. Adaptive physical functioning was measured using two tests: the timed up and go (TUG) test and the physical performance test. Persistent motor neuropathy was measured using the modified total neuropathy score; HRQoL was measured using the Short-Form-36 questionnaire. The associations between obesity and PCI were evaluated using multivariable linear regressions in adult survivors of childhood ALL (n = 1,166) and community controls (n = 491). Then, the associations between PCI, adaptive physical functioning and peripheral neuropathy were examined using multivariable linear regressions. Finally, to determine the association between obesity, and neuropathy on PCI, while accounting for potential lifestyle and treatment confounders, a three model, sequential linear regression was used.ResultsObese individuals (BMI > 40 kg/m2 and excess body fat percentage [males: >25%; females: >33%]) had higher PCI compared to those with normal BMI and body fat percentage (0.56 ± 0.01 vs. 0.49 ± 0.009 beats/meter p 95th percentile of community controls had lower HRQoL compared to un-impaired ALL survivors: 46.9 ± 0.56 vs. 50.4 ± 1.08, respectively (p

Objective The objective is to examine the association between trajectories of childhood residential and school mobility and academic achievement (literacy, numeracy) in Grade 3 using linked whole-population administrative data in Manitoba, Canada. Secondarily, we assessed childhood residential/school mobility based on neighbourhood income levels (moving in/out of low- or mid-/high-income neighbourhoods). Approach This retrospective cohort study used linkable, de-identified administrative data (health, education, national census, provincial survey) from the provincial Population Research Data Repository housed at the Manitoba Centre for Health Policy (MCHP). Among kindergarteners from 2005 to 2014 (n = 83,894), those not having continuous residency in Manitoba, valid education assessments, and relevant family-level covariates were excluded. We followed this eligible cohort from kindergarten to Grade 3 based on various neighbourhood income trajectories of residential and school mobility. To assess Grade 3 literacy and numeracy scores based on trajectories, log-binomial regression models were conducted using SAS® version 9.4. Results The total cohort included 36,754 children; at the end of kindergarten, 14.2% resided in low-income neighbourhoods, and 84.8% lived in mid-/high-income neighbourhoods. Moving between two low-income neighborhoods between kindergarten to Grade 3 was associated with an increased risk of poor Grade 3 numeracy and literacy scores (numeracy aRR=1.39 [1.16,1.67]; literacy aRR=1.31 [1.08,1.59]). When moving between neighborhood income levels, the association was stronger for children moving into low-income neighbourhoods (e.g., mid-/high-income to low-income: numeracy aRR=1.41 [1.19,1.67]) than children moving into mid/high-income neighbourhoods (e.g., low-income to mid-/high-income: numeracy aRR=1.31 [1.08,1.59]). Changing schools between kindergarten and Grade 3 was also associated with poorer numeracy and literacy scores in Grade 3 (numeracy aRR=1.31 [1.22,1.40]; literacy aRR=1.34 [1.24,1.44]); however, the strength varied based on residential mobility patterns. Conclusion Moving homes/schools can differentially impact children’s educational attainment depending upon the income level of residing neighborhood(s). Stakeholders should recognize different levels of risks related to mobility and provide support accordingly to reduce the adverse impact. Support systems should be tailored to not only children but also families and neighbourhoods.

Purpose: Code status orders impact clinical outcomes as well as patients’ and surrogates’ experiences. This is the first multicenter cohort examining code status orders of ICU patients with COVID-19 reported to date. Materials and methods: This is a retrospective cohort study including adult patients who tested positive for SARS-CoV-2 and were admitted to the ICU at three hospitals in Massachusetts from March 11, 2020 - May 31, 2020. We examined differences in code status orders at multiple timepoints and performed multivariable regression analysis to identify variables associated with code status at admission. Results: Among 459 ICU patients with COVID-19, 421 (91.7%) were Full Code at hospital admission. Age and admission from a facility were positively associated with DNR status (adjusted OR 1.10, 95% CI 1.05–1.15, p

Abstract Background It is well-established that cancer treatment substantially increases the risk of long-term adverse health outcomes among childhood cancer survivors. However, there is limited research on the underlying mechanisms. To elucidate the pathophysiology and a possible causal pathway from treatment exposures to cardiometabolic conditions, we conducted epigenome-wide association studies (EWAS) to identify the DNA methylation (DNAm) sites associated with cancer treatment exposures and examined whether treatment-associated DNAm sites mediate associations between specific treatments and cardiometabolic conditions. Methods We included 2052 survivors (median age 33.7 years) of European ancestry from the St. Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Cumulative doses of chemotherapy and region-specific radiation were abstracted from medical records. Seven cardiometabolic conditions were clinically assessed. DNAm profile was measured using MethylationEPIC BeadChip with blood-derived DNA. Results By performing multiple treatment-specific EWAS, we identified 935 5′-cytosine-phosphate-guanine-3′ (CpG) sites mapped to 538 genes/regions associated with one or more cancer treatments at the epigenome-wide significance level (p

High-dose acetaminophen (AAP) with delayed rescue using n-acetylcysteine (NAC), the FDA-approved antidote to AAP overdose, has demonstrated promising antitumor efficacy in early phase clinical trials. However, the mechanism of action (MOA) of AAP's anticancer effects remains elusive. Using clinically relevant AAP concentrations, we evaluated cancer stem cell (CSC) phenotype in vitro and in vivo in lung cancer and melanoma cells with diverse driver mutations. Associated mechanisms were also studied. Our results demonstrated that AAP inhibited 3D spheroid formation, self-renewal, and expression of CSC markers when human cancer cells were grown in serum-free CSC media. Similarly, anti-CSC activity was demonstrated in vivo in xenograft models - tumor formation following in vitro treatment and ex-vivo spheroid formation following in vivo treatment. Intriguingly, NAC, used to mitigate AAP's liver toxicity, did not rescue cells from AAP's anti-CSC effects, and AAP failed to reduce glutathione levels in tumor xenograft in contrast to mice liver tissue suggesting nonglutathione-related MOA. In fact, AAP mediates its anti-CSC effect via inhibition of STAT3. AAP directly binds to STAT3 with an affinity in the low micromolar range and a high degree of specificity for STAT3 relative to STAT1. These findings have high immediate translational significance concerning advancing AAP with NAC rescue to selectively rescue hepatotoxicity while inhibiting CSCs. The novel mechanism of selective STAT3 inhibition has implications for developing rational anticancer combinations and better patient selection (predictive biomarkers) for clinical studies and developing novel selective STAT3 inhibitors using AAP's molecular scaffold.

The Republic of Guatemala’s reported COVID-19 vaccination coverage is among the lowest in the Americas and there are limited studies describing the disparities in vaccine uptake within the country. We performed a cross-sectional ecological analysis using multi-level modeling to identify sociodemographic characteristics that were associated with low COVID-19 vaccination coverage among Guatemalan municipalities as of 30 November 2022. Municipalities with a higher proportion of people experiencing poverty (β = −0.25, 95% CI: −0.43–−0.07) had lower vaccination coverage. Municipalities with a higher proportion of people who had received at least a primary education (β = 0.74, 95% CI: 0.38–1.08), children (β = 1.07, 95% CI: 0.36–1.77), people aged 60 years and older (β = 2.94, 95% CI: 1.70–4.12), and testing for SARS-CoV-2 infection (β = 0.25, 95% CI: 0.14–0.36) had higher vaccination coverage. In the simplified multivariable model, these factors explained 59.4% of the variation in COVID-19 vaccination coverage. Poverty remained significantly associated with low COVID-19 vaccination coverage in two subanalyses restricting the data to the time period of the highest national COVID-19-related death rate and to COVID-19 vaccination coverage only among those aged 60 years or older. Poverty is a key factor associated with low COVID-19 vaccination and focusing public health interventions in municipalities most affected by poverty may help address COVID-19 vaccination and health disparities in Guatemala.

Abstract Background There is currently no method to precisely measure the errors that occur in the sequencing instrument/sequencer, which is critical for next-generation sequencing applications aimed at discovering the genetic makeup of heterogeneous cellular populations. Results We propose a novel computational method, SequencErr, to address this challenge by measuring the base correspondence between overlapping regions in forward and reverse reads. An analysis of 3777 public datasets from 75 research institutions in 18 countries revealed the sequencer error rate to be ~ 10 per million (pm) and 1.4% of sequencers and 2.7% of flow cells have error rates > 100 pm. At the flow cell level, error rates are elevated in the bottom surfaces and > 90% of HiSeq and NovaSeq flow cells have at least one outlier error-prone tile. By sequencing a common DNA library on different sequencers, we demonstrate that sequencers with high error rates have reduced overall sequencing accuracy, and removal of outlier error-prone tiles improves sequencing accuracy. We demonstrate that SequencErr can reveal novel insights relative to the popular quality control method FastQC and achieve a 10-fold lower error rate than popular error correction methods including Lighter and Musket. Conclusions Our study reveals novel insights into the nature of DNA sequencing errors incurred on DNA sequencers. Our method can be used to assess, calibrate, and monitor sequencer accuracy, and to computationally suppress sequencer errors in existing datasets.

This study evaluated false seedbeds, which are sequences of irrigation and tillage that eliminate weed seedlings before crop planting, to reduce requirements for hand hoeing in chile pepper (Capsicum annuum). To address this objective, a field study was conducted near Las Cruces, NM from July 2015 to Oct. 2016 (experimental run 1) and July 2016 to Oct. 2017 (experimental run 2). False seedbeds were designed to target weeds that typically emerge after chile pepper planting. This was done by implementing false seedbeds the summer before chile pepper seeding. During chile pepper seasons, data included repeated measures of weed seedling emergence, amounts of time required for individuals to hoe field sections (i.e., hoeing time), and yields of two chile products: early harvest of green fruit and late harvest of red fruit. Hoeing time and yield data were included in cost–benefit analyses that also incorporated expenses and revenues projected by crop budget models for the study region. Results indicated false seedbeds caused a 54% decrease in weed population density during the chile pepper season of experimental run 1; however, for experimental run 2, false seedbeds did not affect cumulative weed seedling emergence. For both experimental runs, false seedbeds reduced hoeing times, suggesting that false seedbeds affected hoeing by means other than reduced weed density. After accounting for costs for implementation, false seedbeds reduced hand hoeing costs by $262/acre to $440/acre. These reductions in hoeing costs coincided with improved profitability in all but one combination of year and product. Green fruit yield was lower in false seedbed plots in experimental run 1; however, false seedbeds did not affect green fruit yield in experimental run 2, or red fruit yield in both experimental runs. These results indicate that false seedbeds implemented the summer before planting are promising techniques for reducing labor requirements for weeding in chile pepper production.

Stress can increase ethanol drinking, and evidence confirms an association between post-traumatic stress disorder (PTSD) and the development of alcohol use disorder (AUD). Exposure to predator odor is considered a traumatic stressor, and predator stress (PS) has been used extensively as an animal model of PTSD. Our prior work determined that repeated exposure to intermittent PS significantly increased anxiety-related behavior, corticosterone levels, and neuronal activation in the hippocampus and prefrontal cortex in naïve male and female C57BL/6J mice. Intermittent PS exposure also increased subsequent ethanol drinking in a subgroup of animals, with heterogeneity of responses as seen with comorbid PTSD and AUD. The present studies built upon this prior work and began to characterize “sensitivity” and “resilience” to PS-enhanced drinking. Ethanol drinking was measured during baseline, intermittent PS exposure, and post-stress; mice were euthanized after 24-h abstinence. Calculation of median and interquartile ranges identified “sensitive” (>20% increase in drinking over baseline) and “resilient” (no change or decrease in drinking from baseline) subgroups. Intermittent PS significantly increased subsequent ethanol intake in 24% of male (↑60%) and in 20% of female (↑71%) C57BL/6J mice in the “sensitive” subgroup. Plasma corticosterone levels were increased significantly after PS in both sexes, but levels were lower in the “sensitive” vs. “resilient” subgroups. In representative mice from “sensitive” and “resilient” subgroups, prefrontal cortex and hippocampus were analyzed by Western Blotting for levels of corticotropin releasing factor (CRF) receptor 1, CRF receptor 2, CRF binding protein, and glucocorticoid receptor, vs. separate naïve age-matched mice. In prefrontal cortex, CRF receptor 1, CRF receptor 2, CRF binding protein, and glucocorticoid receptor levels were significantly higher in “sensitive” vs. naïve and “resilient” mice only in females. In hippocampus, CRF receptor 1, CRF receptor 2 and glucocorticoid receptor levels were significantly lower in “resilient” vs. naïve and “sensitive” mice across both sexes. These results indicate that sex strongly influences the effects of ethanol drinking and stress on proteins regulating stress and anxiety responses. They further suggest that targeting the CRF system and glucocorticoid receptors in AUD needs to consider the comorbidity of PTSD with AUD and sex of treated individuals.

The Asenze cohort is set in South Africa, a middle-income country impacted by one of the highest global rates of people living with HIV/AIDS and high levels of socioeconomic inequality. This longitudinal population-based cohort of children and their primary caregivers assesses household and caregiver functioning, child health, social well-being, and neuro-development from childhood through adolescence. Almost 1,600 children born at the peak of the human immunodeficiency virus epidemic (2003-2005) were followed (with their primary caregivers) in 3 waves, between 2008 and 2021, at average ages of 5, 7, and 16. Wave 3 is currently underway, having assessed over 1,100 of the original wave 1 children. Wave 4 begins in 2022. The study, with a dyadic structure, uses a broad range of measures, validated in South Africa or recommended for global use, that address physical, social and neuro-development in childhood and adolescence, and the social, health, and psychological status of children’s primary caregivers. The Asenze study deepens our understanding of childhood physical, cognitive, and social abilities and/or disabilities, including risk-taking behaviors, and biological, environmental, and social determinants of health. We anticipate the findings will contribute to the development of community-informed interventions to promote well-being in this South African population and elsewhere.

Kojic acid (KA) is a fungal metabolite and has a variety of applications in the cosmetics and food industries. Aspergillus oryzae is a well-known producer of KA, and its KA biosynthesis gene cluster has been identified. In this study, we showed that nearly all section Flavi aspergilli except for A. avenaceus had complete KA gene clusters, and only one Penicillium species, P. nordicum, contained a partial KA gene cluster. Phylogenetic inference based on KA gene cluster sequences consistently grouped section Flavi aspergilli into clades as prior studies. The Zn(II)2Cys6 zinc cluster regulator KojR transcriptionally activated clustered genes of kojA and kojT in Aspergillus flavus. This was evidenced by the time-course expression of both genes in kojR-overexpressing strains whose kojR expression was driven by a heterologous Aspergillus nidulans gpdA promoter or a homologous A. flavus gpiA promoter. Using sequences from the kojA and kojT promoter regions of section Flavi aspergilli for motif analyses, we identified a consensus KojR-binding motif to be an 11-bp palindromic sequence of 5′-CGRCTWAGYCG-3′ (R = A/G, W = A/T, Y = C/T). A CRISPR/Cas9-mediated gene-targeting technique showed that the motif sequence, 5′-CGACTTTGCCG-3′, in the kojA promoter was critical for KA biosynthesis in A. flavus. Our findings may facilitate strain improvement and benefit future kojic acid production.

BackgroundAssessing patient-reported outcomes (PROs) through interviews or conversations during clinical encounters provides insightful information about survivorship. ObjectiveThis study aims to test the validity of natural language processing (NLP) and machine learning (ML) algorithms in identifying different attributes of pain interference and fatigue symptoms experienced by child and adolescent survivors of cancer versus the judgment by PRO content experts as the gold standard to validate NLP/ML algorithms. MethodsThis cross-sectional study focused on child and adolescent survivors of cancer, aged 8 to 17 years, and caregivers, from whom 391 meaning units in the pain interference domain and 423 in the fatigue domain were generated for analyses. Data were collected from the After Completion of Therapy Clinic at St. Jude Children’s Research Hospital. Experienced pain interference and fatigue symptoms were reported through in-depth interviews. After verbatim transcription, analyzable sentences (ie, meaning units) were semantically labeled by 2 content experts for each attribute (physical, cognitive, social, or unclassified). Two NLP/ML methods were used to extract and validate the semantic features: bidirectional encoder representations from transformers (BERT) and Word2vec plus one of the ML methods, the support vector machine or extreme gradient boosting. Receiver operating characteristic and precision-recall curves were used to evaluate the accuracy and validity of the NLP/ML methods. ResultsCompared with Word2vec/support vector machine and Word2vec/extreme gradient boosting, BERT demonstrated higher accuracy in both symptom domains, with 0.931 (95% CI 0.905-0.957) and 0.916 (95% CI 0.887-0.941) for problems with cognitive and social attributes on pain interference, respectively, and 0.929 (95% CI 0.903-0.953) and 0.917 (95% CI 0.891-0.943) for problems with cognitive and social attributes on fatigue, respectively. In addition, BERT yielded superior areas under the receiver operating characteristic curve for cognitive attributes on pain interference and fatigue domains (0.923, 95% CI 0.879-0.997; 0.948, 95% CI 0.922-0.979) and superior areas under the precision-recall curve for cognitive attributes on pain interference and fatigue domains (0.818, 95% CI 0.735-0.917; 0.855, 95% CI 0.791-0.930). ConclusionsThe BERT method performed better than the other methods. As an alternative to using standard PRO surveys, collecting unstructured PROs via interviews or conversations during clinical encounters and applying NLP/ML methods can facilitate PRO assessment in child and adolescent cancer survivors.

The five-year survival rate of childhood cancer has increased substantially over the past 50 yr; however, racial/ethnic disparities in health outcomes of survival have not been systematically reviewed. This scoping review summarized health disparities between racial/ethnic minorities (specifically non-Hispanic Black and Hispanic) and non-Hispanic White childhood cancer survivors, and elucidated factors that may explain disparities in health outcomes. We used the terms “race”, “ethnicity”, “childhood cancer”, “pediatric cancer”, and “survivor” to search the title and abstract for the articles published in PubMed and Scopus from inception to February 2021. After removing duplicates, 189 articles were screened, and 23 empirical articles were included in this review study. All study populations were from North America, and the mean distribution of race/ethnicity was 6.9% for non-Hispanic Black and 4.5% for Hispanic. Health outcomes were categorized as healthcare utilization, patient-reported outcomes, chronic health conditions, and survival status. We found robust evidence of racial/ethnic disparities over four domains of health outcomes. However, health disparities were explained by clinical factors (e.g., diagnosis, treatment), demographic (e.g., age, sex), individual-level socioeconomic status (SES; e.g., educational attainment, personal income, health insurance coverage), family-level SES (e.g., family income, parent educational attainment), neighborhood-level SES (e.g., geographic location), and lifestyle health risk (e.g., cardiovascular risk) in some but not all articles. We discuss the importance of collecting comprehensive social determinants of racial/ethnic disparities inclusive of individual-level, family-level, and neighborhood-level SES. We suggest integrating these variables into healthcare systems (e.g., electronic health records), and utilizing information technology and analytics to better understand the disparity gap for racial/ethnic minorities of childhood cancer survivors. Furthermore, we suggest national and local efforts to close the gap through improving health insurance access, education and transportation aid, racial-culture-specific social learning interventions, and diversity informed training.

Family health history is a well-established risk factor for many health conditions but the systematic collection of health histories, particularly for multiple generations and multiple family members, can be challenging. Routinely-collected electronic databases in a select number of sites worldwide offer a powerful tool to conduct multigenerational health research for entire populations. At these sites, administrative and healthcare records are used to construct familial relationships and objectively-measured health histories. We review and synthesize published literature to compare the attributes of routinely-collected, linked databases for three European sites (Denmark, Norway, Sweden) and three non-European sites (Canadian province of Manitoba, Taiwan, Australian state of Western Australia) with the capability to conduct population-based multigenerational health research. Our review found that European sites primarily identified family structures using population registries, whereas non-European sites used health insurance registries (Manitoba and Taiwan) or linked data from multiple sources (Western Australia). Information on familial status was reported to be available as early as 1947 (Sweden); Taiwan had the fewest years of data available (1995 onwards). All centres reported near complete coverage of familial relationships for their population catchment regions. Challenges in working with these data include differentiating biological and legal relationships, establishing accurate familial linkages over time, and accurately identifying health conditions. This review provides important insights about the benefits and challenges of using routinely-collected, population-based linked databases for conducting population-based multigenerational health research, and identifies opportunities for future research within and across the data-intensive environments at these six sites.

In 2017, two new tomato mosaic virus (ToMV) isolates were collected from greenhouses in Buyeo, Chungcheongnam-do, South Korea. Full-length cDNAs of the new ToMV isolates were cloned into dual cauliflower mosaic virus 35S and T7 promoter-driven vectors, sequenced and their pathogenicities investigated. The nucleotide sequences of isolates GW1 (MH507165) and GW2 (MH507166) were 99% identical, resulting in only two amino acid differences in nonconserved region II and the helicase domain, Ile668Thr and Val834Ile. The two isolates were most closely related to a ToMV isolate from Taiwan (KJ207374). Isolate GW1 (Ile668, Val834) induced a systemic hypersensitive response in Nicotiana benthamiana compared with the isolate GW2, which a single residue substitution showed was due to Val834.

For several years, temperatures in the Korean peninsula have gradually increased due to climate change, resulting in a changing environment for growth of crops and vegetables. An associated consequence is that emerging species of insect vector have caused increased viral transmission. In Jeju Island, Korea, occurrences of viral disease have increased. Here, we report characterization of five newly collected turnip mosaic virus (TuMV) isolates named KBJ1, KBJ2, KBJ3, KBJ4 and KBJ5 from a survey on Jeju Island in 2017. Full-length cDNAs of each isolate were cloned into the pJY vector downstream of cauliflower mosaic virus 35S and bacteriophage T7 RNA polymerase promoters. Their fulllength sequences share 98.9–99.9% nucleotide sequence identity and were most closely related to previously reported Korean TuMV isolates. All isolates belonged to the BR group and infected both Chinese cabbage and radish. Four isolates induced very mild symptoms in Nicotiana benthamiana but KBJ5 induced a hypersensitive response. Symptom differences may result from three amino acid differences uniquely present in KBJ5; Gly(382)Asp, Ile(891)Val, and Lys(2522)Glu in P1, P3, and NIb, respectively.

Abstract Background Previous studies have reported an intergenerational association between maternal and offspring preterm birth (PTB) but the nature of the association remains unclear. We assessed the association between maternal and offspring preterm birth using a quasi-experimental sibling design and distinguishing between preterm birth types. Methods We conducted a retrospective intergenerational cohort study of 39,573 women born singleton in Manitoba, Canada (1980–2002) who gave birth to 79,198 singleton infants (1995–2016). To account for familial confounding we defined a subcohort of 1033 sisters with discordant PTB status who subsequently gave birth and compared offspring PTB rates between 2499 differentially exposed cousins using log-binomial fixed-effects generalized estimating equation models. PTB was defined as a delivery

Abstract Background Sequencing errors are key confounding factors for detecting low-frequency genetic variants that are important for cancer molecular diagnosis, treatment, and surveillance using deep next-generation sequencing (NGS). However, there is a lack of comprehensive understanding of errors introduced at various steps of a conventional NGS workflow, such as sample handling, library preparation, PCR enrichment, and sequencing. In this study, we use current NGS technology to systematically investigate these questions. Results By evaluating read-specific error distributions, we discover that the substitution error rate can be computationally suppressed to 10−5 to 10−4, which is 10- to 100-fold lower than generally considered achievable (10−3) in the current literature. We then quantify substitution errors attributable to sample handling, library preparation, enrichment PCR, and sequencing by using multiple deep sequencing datasets. We find that error rates differ by nucleotide substitution types, ranging from 10−5 for A>C/T>G, C>A/G>T, and C>G/G>C changes to 10−4 for A>G/T>C changes. Furthermore, C>T/G>A errors exhibit strong sequence context dependency, sample-specific effects dominate elevated C>A/G>T errors, and target-enrichment PCR led to ~ 6-fold increase of overall error rate. We also find that more than 70% of hotspot variants can be detected at 0.1 ~ 0.01% frequency with the current NGS technology by applying in silico error suppression. Conclusions We present the first comprehensive analysis of sequencing error sources in conventional NGS workflows. The error profiles revealed by our study highlight new directions for further improving NGS analysis accuracy both experimentally and computationally, ultimately enhancing the precision of deep sequencing.

Winning the war against worms A broad genomic mapping effort in the common bean reveals sequence elements that may help protect this crop from plant-killing worms. The soybean cyst nematode has the potential to wreak havoc on the common bean, an important food source in many countries. Researchers led by Glen Hartman at the US Department of Agriculture conducted an extensive survey of 363 different derivatives of this crop in order to identify genetic features that might confer resistance against two different strains of this infectious worm. Their study identified regions on three different chromosomes that each appear to contribute some degree of protection against soybean cyst nematode. These offer starting points for understanding the molecular foundations of pest resistance in this crop, and could facilitate the future breeding of more robust bean strains.

Urbanization disrupts landscapes and ecosystem functions, which poses threats to biodiversity, social systems, and human health, particularly among vulnerable populations. Urban land-use planners are faced with competing demands for housing, safety, transportation, and economic development and often lack tools to integrate these with protecting environmental functions. We identify three major barriers to integrating the benefits that flow with connected, functioning ecosystems into land-use planning. The lack of a shared language among planners and stakeholders poses a barrier to the restoration and preservation of ecological features. Methods of incorporating the benefits from connectivity are not standardized because values are not readily available or lack credibility. Ecological restoration tends to be poorly coordinated at broad scales, and thus often fails to achieve landscape-level objectives. To address these challenges, we developed a novel integrated framework, the Connectivity Benefits Framework (CBF), which combines the benefits from three categories of ecosystem connectivity with benefit- and risk-relevant indicators, enabling both monetary and non-monetary valuation of benefits. Moreover, it provides a method to identify and visualize the multiple and overlapping benefits from management actions to aid in prioritizing initiatives that support ecosystem functions. Unlike software tools that incorporate generalized values of ecosystem services at a landscape level, the CBF guides a systematic approach to community-engaged land-use planning that prioritizes localized societal needs while protecting biodiversity and ecosystem function for more equitable, resilient cities. We demonstrate the potential for multiple overlapping benefits from actions that restore and protect ecosystem connectivity by applying the framework to a transit planning project in Portland, Oregon.

Introduction Major osteoporotic fractures (MOF) are associated with significant morbidity and healthcare system burden. Objectives and Approach We aimed to determine whether sibling fracture history is associated with MOF risk amongst individuals from a population-based cohort using objectively-ascertained measures of fracture history. This retrospective cohort study used administrative databases from the province of Manitoba, Canada, which has a universal healthcare system. The cohort included individuals aged 40 years and older between 1997 and 2015 with linkage to at least one sibling. The exposure was MOF diagnosis occurring at age 40 years or older in a randomly selected sibling. The outcome was incident clinically-diagnosed MOF (hip, wrist, humerus or spine) identified in hospital and physician records using established case definitions. A multivariable Cox proportional hazards regression was used to test the association of sibling fracture history with the risk of MOF in individuals after adjustment for known fracture risk factors. Results The cohort included 217,519 individuals; 92% were linked to full siblings (i.e., same mother/father) and 49% were females. During a median follow-up of 11 years (IQR 5 -15), 7274 (3.3%) incident MOF cases were identified. Sibling MOF history was associated with increased risk of MOF (HR 1.71, 95% CI 1.48–1.97). The risk was elevated in both men (HR 1.63, 95% CI 1.29-2.06) and women (HR 1.78, 95% CI 1.48-2.13) but was higher among sisters (HR 2.08, 95% CI 1.65-2.61) compared to brothers (HR 1.67, 95% CI 1.20-2.32). In a secondary analysis of sibling fracture site, the highest risk was observed with diagnosis of wrist followed by spine fractures (HR 1.86, 95% CI 1.57-2.21 and HR 1.46, 95% CI 1.08-1.98, respectively). Conclusion Sibling fracture history is associated with increased MOF risk in individuals and should be considered as a candidate risk factor for improving fracture risk prediction.

Introduction Studies on the relationship between exposure to maternal depression in early childhood and childhood development have been limited by small samples, lack of information on timing of maternal depression, and use of a composite measure of childhood development. Objectives and Approach We linked multiple Manitoba datasets to examine the relationship between exposure to maternal depression in early childhood and childhood development at school entry across five domains, and age at exposure to maternal depression on developmental outcomes using a population-based cohort (n = 52,103). Maternal depression was defined using physician visits, hospitalizations, and pharmaceutical data, while developmental vulnerability was assessed using the well-validated Early Development Instrument. Relative risk of developmental vulnerability was assessed using log-binomial regression models, adjusted for maternal and childhood characteristics at the birth of the child. Results Children exposed to maternal depression before age 5 had a 17% higher risk of having at least one developmental vulnerability at school entry than children not exposed to such depression before age 5. Exposure to maternal depression before age 5 was most strongly associated with social competence (aRR = 1.28, 95% CI 1.20, 1.38), physical health and well-being (aRR = 1.28, 95% CI 1.20, 1.36), and emotional maturity (aRR = 1.27, 95% CI 1.18, 1.37). For most developmental domains, exposure to maternal depression before age 1 and between ages 4 and 5 had the greatest association with developmental vulnerability. Conclusion / Implications Our findings that children exposed to maternal depression were at higher risk of developmental vulnerability at school entry is consistent with previous studies. However, we found that the association between exposure to maternal depression and development varied across developmental domains, and the relationship varied depending on the age of exposure to maternal depression. Ongoing analyses of discordant cousins will shed more light on the causal nature of this relationship.