Maternal Prenatal Use of Alcohol, Tobacco, and Illicit Drugs and Associations with Childhood Cancer Subtypes.

BACKGROUND: The association between childhood cancer risk and maternal prenatal substance use/abuse remains uncertain due to modest sample sizes and heterogeneous study designs. METHODS: We surveyed parents of children with cancer regarding maternal gestational use of tobacco, alcohol, and illicit drugs, using a Likert-type scale, and demographic, perinatal, and clinical variables. Multivariable log-Poisson regression assessed differences in frequency of prenatal substance use across fifteen childhood cancer subtypes, adjusting for birthweight, gestational age, and demographic factors. RESULTS: Respondents from 3,145 unique families completed the survey (92% biological mothers). A minority reported gestational use of tobacco products (14%), illicit drugs including marijuana or cocaine (4%), or more than a moderate amount of alcohol (2%). Prenatal illicit drug use was associated with increased prevalence of intracranial embryonal tumors [prevalence ratio (PR) = 1.94; confidence interval [CI], 1.05-3.58], including medulloblastoma (PR = 1.82) and supratentorial primitive neuroectodermal tumors (PNET; PR = 2.66), and was also associated with retinoblastoma (PR = 3.11; CI, 1.20-8.08). Moderate to heavy alcohol consumption was strongly associated with elevated prevalence of non-Hodgkin lymphoma (PR = 5.94; CI, 1.84-19.21). Prenatal smoking was not associated with elevated prevalence of any childhood cancer subtype. CONCLUSIONS: We identify novel associations between illicit drug use during pregnancy and increased prevalence of nonglioma central nervous system tumors, including medulloblastoma, supratentorial PNETs, and retinoblastoma. Gestational exposure to alcohol was positively associated with non-Hodgkin lymphoma. IMPACT: Although alcohol and tobacco use during pregnancy has declined, gestational cannabis use has risen. Investigating its impact on neurodevelopment and brain tumorigenesis is vital, with important implications for childhood cancer research and public health education.

Beyond Anxiety and Grief: Mapping the Emotional Landscape of Parents Facing a Childhood Cancer Diagnosis.

Objective: We sought to explore the variation in emotional responses and identify clusters of emotional patterns associated with sociodemographic, clinical, and familial factors. Methods: A large-scale survey with questions on demographics, experiences, and emotions at the time of diagnosis was sent to childhood cancer caregivers and completed between August 2012 and April 2019. Dimensionality reduction and statistical tests for independence were used to investigate relationships between sociodemographic, clinical, and psychosocial factors and 32 representative emotions. Results: Data from 3142 respondents were analyzed. Through principal components analysis and t-distributed stochastic neighbor embedding analysis, three clusters of emotional responses were identified, captured 44%, 20% and 36% of respondents, respectively. Hallmark emotions within each cluster were "anger and grief" (Cluster 1), "pessimism, relief, impatience, insecurity, discouragement, and calm" (Cluster 2), and "hope" (Cluster 3). Cluster membership was associated with differences in parental factors, such as educational attainment, family income, and biological parent status, as well as child-specific factors, including age at diagnosis and cancer type. Conclusions: The study revealed substantial heterogeneity in emotional responses to a child's cancer diagnosis than previously recognized, with differences linked to both caregiver and child-related factors. These findings underscore the importance of developing responsive and effective programs to improve targeted support for caregivers from the time of diagnosis throughout a family's childhood cancer journey.

The joint impacts of sex and race/ethnicity on incidence of grade 1 versus grades 2-3 meningioma across the lifespan.

Background: Previous research has identified older age, African-American race, and female sex as meningioma risk factors, but there is limited information on their joint effects, or on how these demographic factors vary across strata of tumor grade. Methods: The Central Brain Tumor Registry of the United States (CBTRUS) is a population-based registry combining data from the CDC's National Program of Cancer Registries and NCI's Surveillance, Epidemiology and End Results Program which covers ~100% of the U.S. population and aggregates incidence data on all primary malignant and nonmalignant brain tumors. These data were used to explore the joint impacts of sex and race/ethnicity on average annual age-adjusted incidence rates of meningioma. We calculated meningioma incidence rate ratios (IRRs) by sex and race/ethnicity, across strata of age and tumor grade. Results: Compared to individuals who are non-Hispanic White, individuals who are non-Hispanic Black had significantly higher risk of grade 1 (IRR = 1.23; 95% CI: 1.21-1.24) and grade 2-3 meningioma (IRR = 1.42; 95% CI: 1.37-1.47). The female-to-male IRR peaked in the fifth decade of life across all racial/ethnic groups and tumor grades, but was 3.59 (95% CI: 3.51-3.67) for WHO grade 1 meningioma and 1.74 (95% CI: 1.63-1.87) for WHO grade 2-3 meningioma. Conclusions: This study reveals the joint effects of sex and race/ethnicity on meningioma incidence throughout the lifespan and across strata of tumor grade, highlighting incidence disparities among females and African-Americans that may inform future strategies for tumor interception.

Systematic review and meta-analysis of the effect of adverse childhood experiences (ACEs) on brain-derived neurotrophic factor (BDNF) levels.

There is continued interest in identifying dysregulated biomarkers that mediate associations between adverse childhood experiences (ACEs) and negative long-term health outcomes. However, little is known regarding how ACE exposure modulates neural biomarkers to influence poorer health outcomes in ACE-exposed children. To address this, we performed a systematic review and meta-analysis of the impact of ACE exposure on Brain Derived Neurotrophic Factor (BDNF) levels - a neural biomarker involved in childhood and adult neurogenesis and long-term memory formation. Twenty-two studies were selected for inclusion within the systematic review, ten of which were included in meta-analysis. Most included studies retrospectively assessed impacts of childhood maltreatment in clinical populations. Sample size, BDNF protein levels in ACE-exposed and unexposed subjects, and standard deviations were extracted from ten publications to estimate the BDNF ratio of means (ROM) across exposure categories. Overall, no significant difference was found in BDNF protein levels between ACE-exposed and unexposed groups (ROM: 1.08; 95 % CI: 0.93-1.26). Age at sampling, analyte type (e.g., sera, plasma, blood), and categories of ACE exposure contributed to high between-study heterogeneity, some of which was minimized in subset-based analyses. These results support continued investigation into the impact of ACE exposure on neural biomarkers and highlight the potential importance of analyte type and timing of sample collection on study results.

Financial hardships and psychosocial outcomes among parents of children who die of cancer.

BACKGROUND: Caregivers experience financial hardship during a child's cancer treatment and after their child's death. These bereaved caregivers also experience negative psychosocial outcomes following the death of a child, but the relationship between financial hardship and negative psychosocial outcomes is poorly understood in this population. METHODS: We surveyed self-selected bereaved caregivers as part of a publicly posted survey through Alex's Lemonade Stand Foundation in order to explore family experiences after losing a child to cancer. The survey contained questions regarding parent psychosocial and financial outcomes following their child's death. RESULTS: One-hundred seventy-six caregivers completed the survey a median of 7 years after their child's death. The majority were female (91%), non-Hispanic White (97%), and married or living with a domestic partner (76%). Overall, 31% of caregivers reported that their child's death significantly impacted the financial well-being of their family, 23% experienced a decrease in income following their child's death, and 14% were still paying medical expenses. Financial hardship that the caregiver attributed to the child's death was associated with feeling lonely and isolated (adjusted relative risk [ARR] = 1.7, 95% CI: 1.1-2.7) and living day to day (ARR = 1.8, 95% CI: 1.3-2.5), even after adjustment for household income and time since child's death. CONCLUSIONS: Caregivers experience multiple financial hardships following the death of a child to cancer, which endure for years after the child's death. These hardships are associated with negative psychosocial outcomes, demonstrating the need for both financial and psychosocial interventions for caregivers following the death of a child to cancer.

Assisted reproductive technology and association with childhood cancer subtypes.

OBJECTIVES: To investigate the association between assisted reproductive technology (ART) use and childhood cancer subtype. STUDY DESIGN: We deployed a cross-sectional survey of 1701 parents of children with cancer about their ART use, demographics, and gestational and perinatal factors. Multivariable logistic regression modeled the association between ART use, birthweight and multiple gestation status with childhood cancer, by subtype. RESULTS: ART use was highest among children with osteosarcoma relative to children with other cancer types, and this association was statistically significant in multivariable models (OR = 4.4; 95% CI = 1.7-11.3; p = 0.0020). ART use was also elevated among children with hepatoblastoma, but this relationship appeared to be due to the strong associations between ART use and lower birthweight in our sample. No specific ART modality appeared to drive these associations. In univariate models, multiple gestation was associated with a 2.7-fold increased odds of hepatoblastoma (OR = 2.71; 95% CI = 1.14-6.42; p = 0.02) and a 1.6-fold increased odds of neuroblastoma (OR = 1.62; 95% CI = 1.03-2.54; p = 0.03), but these associations were not retained in multivariable models. CONCLUSIONS: Associations between ART use and hepatoblastoma risk may be attributable to birthweight, a known hepatoblastoma risk factor. ART use may also be associated with osteosarcoma, independent of birthweight, an association not previously observed in studies limited to cancers diagnosed before adolescence. Evaluating long-term health outcomes in children conceived by ART, throughout adolescence and potentially into adulthood, appears warranted.

Maternal Fc-mediated non-neutralizing antibody responses correlate with protection against congenital human cytomegalovirus infection.

Human cytomegalovirus (HCMV) is the most common congenital infection and a leading cause of stillbirth, neurodevelopmental impairment, and pediatric hearing loss worldwide. Development of a maternal vaccine or therapeutic to prevent congenital HCMV has been hindered by limited knowledge of the immune responses that protect against HCMV transmission in utero. To identify protective antibody responses, we measured HCMV-specific IgG binding and antiviral functions in paired maternal and cord blood sera from HCMV-seropositive transmitting (n = 41) and non-transmitting (n = 40) mother-infant dyads identified via a large, US-based, public cord blood bank. We found that high-avidity IgG binding to HCMV and antibody-dependent cellular phagocytosis (ADCP) were associated with reduced risk of congenital HCMV infection. We also determined that HCMV-specific IgG activation of FcγRI and FcγRII was enhanced in non-transmitting dyads and that increased ADCP responses were mediated through both FcγRI and FcγRIIA expressed on human monocytes. These findings suggest that engagement of FcγRI/FcγRIIA and Fc effector functions including ADCP may protect against congenital HCMV infection. Taken together, these data can guide future prospective studies on immune correlates against congenital HCMV transmission and inform HCMV vaccine and immunotherapeutic development.

An integrated genome and phenome-wide association study approach to understanding Alzheimer's disease predisposition.

Genome-wide association studies (GWAS) have identified common single nucleotide polymorphisms (SNPs) that increase late-onset Alzheimer's disease (LOAD) risk. To identify additional LOAD-associated variants and provide insight into underlying disease biology, we performed a phenome-wide association study on 23 known LOAD-associated SNPs and 4:1 matched control SNPs using UK Biobank data. LOAD-associated SNPs were significantly enriched for associations with 8/778 queried traits, including 3 platelet traits. The strongest enrichment was for platelet distribution width (PDW) (p = 1.2 × 10-5), but increased PDW was not associated with LOAD susceptibility in Mendelian randomization analysis. Of 384 PDW-associated SNPs identified by prior GWAS, 36 were nominally associated with LOAD risk (17,008 cases; 37,154 controls) and 5 survived false-discovery rate correction. Associations confirmed known LOAD risk loci near PICALM, CD2AP, SPI1, and NDUFAF6, and identified a novel risk locus in epidermal growth factor receptor. Integrating GWAS and phenome-wide association study data reveals substantial pleiotropy between genetic determinants of LOAD and of platelet morphology, and for the first time implicates epidermal growth factor receptor - a mediator of ß-amyloid toxicity - in Alzheimer's disease susceptibility.

SARS-CoV-2 vaccine acceptability among caregivers of childhood cancer survivors.

OBJECTIVE: To explore willingness/hesitancy to vaccinate self and children against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among caregivers of childhood cancer survivors (CCS). METHODS: A 19-question survey was sent to caregivers of CCS and completed between February 25 and April 13, 2021. Logistic regression was used to investigate relationships between willingness/hesitancy to vaccinate (a) self and (b) CCS, and demographic variables, confidence in the government and medical community's responses to coronavirus disease 2019 (COVID-19), and factors specific to the CCS community (e.g., previous participation in an investigational therapeutic trial). RESULTS: Caregivers (6% male) from 130 unique families completed the survey. Mean CCS age at survey was 15 years (SD 6.4). Mean CCS age at diagnosis was 4.3 years (SD 4.3). Mean time from CCS diagnosis to survey completion was 10 years (SD 6.2). Twenty-one percent of caregivers expressed hesitancy to vaccinate themselves and 29% expressed hesitancy to vaccinate their CCS. Caregivers expressing confidence in the federal government's response to COVID-19 were six-fold likelier to express willingness to self-vaccinate (p < .001) and were three-fold likelier to express willingness to vaccinate their CCS (p = .011). Qualitative analysis of free-text responses revealed three general themes, including (a) confidence in science, medicine, and vaccination as a strategy for health promotion, (b) confidence in SARS-CoV-2 vaccination and belief that CCS are at greater risk of COVID-19 complications, and (c) concerns about the swiftness of COVID-19 vaccine development and insufficient safety/efficacy data in children and CCS. CONCLUSIONS: Results underscore the need for COVID-19 vaccination education and outreach, even among families highly engaged with the medical community, and emphasize the importance of updating these families as relevant data emerge from vaccine trials and registries.

Mental well-being in Sri Lankan medical students: a cross-sectional study.

Preventing burnout and promoting positive mental health among medical students is important. Relevant research is lacking on positive mental health in medical students, particularly in low- and middle-income countries. We conducted a cross-sectional survey of Sri Lankan students enrolled in a five-year medical program. Measures included the Mental Health Continuum-Short Form, Kessler 10 Psychological Distress Scale, and Oldenburg Burnout Inventory. We investigated relationships between year in program, mental health indicators, and academic performance. Three hundred twenty-seven students participated (35% response rate). Most students had moderate positive mental health (64.8%) and severe psychological distress (40.4%). Final year students reported more psychological distress and burnout than first year students. Female students had higher burnout scores than males. In multivariable models, fourth and fifth year students evidenced lower positive mental health than first year students. Mental health indicators were unassociated with academic performance. Overall, distress rates were higher than those reported among students in other countries. Higher burnout and distress may be driven by increased responsibilities in the final clinical years of training. Bolstering positive mental health through positive emotions, meaning, and social connection may minimize burnout and distress, although extracurricular activities require time. Interventions to reduce medical student distress in Sri Lanka are needed.

Impacts of COVID-19 on caregivers of childhood cancer survivors.

PURPOSE: We sought to assess the impact of disruptions due to coronavirus disease 2019 (COVID-19) on caregivers of childhood cancer survivors. METHODS: A 13-question survey containing multiple-choice, Likert-type, and free-text questions on experiences, behaviors, and attitudes during the COVID-19 outbreak was sent to childhood cancer caregivers and completed between April 13 and May 17, 2020. Ordered logistic regression was used to investigate relationships between demographics, COVID-related experiences, and caregiver well-being. RESULTS: Caregivers from 321 unique families completed the survey, including 175 with children under active surveillance/follow-up care and 146 with children no longer receiving oncology care. Overall, caregivers expressed exceptional resiliency, highlighting commonalities between caring for a child with cancer and adopting COVID-19 prophylactic measures. However, respondents reported delayed/canceled appointments (50%) and delayed/canceled imaging (19%). Eleven percent of caregivers reported struggling to pay for basic needs, which was associated with greater disruption to daily life, greater feelings of anxiety, poorer sleep, and less access to social support (p < .05). Caregivers who were self-isolating reported greater feelings of anxiety and poorer sleep (p < .05). Respondents who expressed confidence in the government response to COVID-19 reported less disruption to their daily life, decreased feelings of depression and anxiety, better sleep, and greater hopefulness (p < .001) CONCLUSIONS: Caregivers are experiencing changes to medical care, financial disruptions, and emotional distress due to COVID-19. To better serve caregivers and medically at-risk children, clinicians must evaluate financial toxicity and feelings of isolation in families affected by childhood cancer, and work to provide reliable information on how COVID-19 may differentially impact their children.