Smartphone-based Ecological Momentary Assessment to study "scanxiety" among Adolescent and Young Adult survivors of childhood cancer: A feasibility study.

OBJECTIVE: Scan-related anxiety ("scanxiety") refers to the fear, stress, and anxiety in anticipation of tests and scans in follow-up cancer care. This study assessed the feasibility of Ecological Momentary Assessment (EMA) for real-world, real-time capture of scanxiety using patients' personal smartphone. METHODS: Adolescent and Young Adult survivors of childhood cancer were prompted to complete EMA surveys on a smartphone app three times per day for 11 days (33 surveys total) around their routine surveillance scans. Participants provided structured feedback on the EMA protocol. RESULTS: Thirty out of 46 contacted survivors (65%) enrolled, exceeding the preregistered feasibility cutoff of 55%. The survey completion rate (83%) greatly exceeded the preregistered feasibility cutoff of 65%. Participants generally found the smartphone app easy and enjoyable to use and reported low levels of distress from answering surveys. Participants reported significantly more daily fear of cancer recurrence (FCR) and negative affect in the days before compared to the days after surveillance scans, aligning with the expected trajectory of scanxiety. Participants who reported greater FCR and scanxiety using comprehensive measures at baseline also reported significantly more daily FCR around their surveillance scans, indicating validity of EMA items. Bodily threat monitoring was prospectively and concurrently associated with daily FCR, thus warranting further investigation as a risk factor for scanxiety. CONCLUSIONS: Findings indicate the feasibility, acceptability, and validity of EMA as a research tool to capture the dynamics and potential risk factors for scanxiety.

Bayesian estimation of genetic regulatory effects in high-throughput reporter assays.

MOTIVATION: High-throughput reporter assays dramatically improve our ability to assign function to noncoding genetic variants, by measuring allelic effects on gene expression in the controlled setting of a reporter gene. Unlike genetic association tests, such assays are not confounded by linkage disequilibrium when loci are independently assayed. These methods can thus improve the identification of causal disease mutations. While work continues on improving experimental aspects of these assays, less effort has gone into developing methods for assessing the statistical significance of assay results, particularly in the case of rare variants captured from patient DNA. RESULTS: We describe a Bayesian hierarchical model, called Bayesian Inference of Regulatory Differences, which integrates prior information and explicitly accounts for variability between experimental replicates. The model produces substantially more accurate predictions than existing methods when allele frequencies are low, which is of clear advantage in the search for disease-causing variants in DNA captured from patient cohorts. Using the model, we demonstrate a clear tradeoff between variant sequencing coverage and numbers of biological replicates, and we show that the use of additional biological replicates decreases variance in estimates of effect size, due to the properties of the Poisson-binomial distribution. We also provide a power and sample size calculator, which facilitates decision making in experimental design parameters. AVAILABILITY AND IMPLEMENTATION: The software is freely available from www.geneprediction.org/bird. The experimental design web tool can be accessed at http://67.159.92.22:8080. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Perfluorobutane sulfonate exposure disrupted human placental cytotrophoblast cell proliferation and invasion involving in dysregulating preeclampsia related genes.

We reported that maternal PFBS, an emerging pollutant, exposure is positively associated with preeclampsia which can result from aberrant trophoblasts invasion and subsequent placental ischemia. In this study, we investigated the effects of PFBS on trophoblasts proliferation/invasion and signaling pathways. We exposed a human trophoblast line, HTR8/SVneo, to PFBS. Cell viability, proliferation, and cell cycle were evaluated by the MTS assay, Ki-67 staining, and flow cytometry, respectively. We assessed cell migration and invasion with live-cell imaging-based migration assay and matrigel invasion assay, respectively. Signaling pathways were examined by Western blot, RNA-seq, and qPCR. PFBS exposure interrupted cell proliferation and invasion in a dose-dependent manner. PFBS (100 µM) did not cause cell death but instead significant cell proliferation without cell cycle disruption. PFBS (10 and 100 µM) decreased cell migration and invasion, while PFBS (0.1 µM) significantly increased cell invasion but not migration. Further, RNA-seq analysis identified dysregulated HIF-1α target genes that are relevant to cell proliferation/invasion and preeclampsia, while Western Blot data showed the activation of HIF-1α, but not Notch, ERK1/2, (PI3K)AKT, and P38 pathways. PBFS exposure altered trophoblast cell proliferation/invasion which might be mediated by preeclampsia-related genes, suggesting a possible association between prenatal PFBS exposure and adverse placentation.

Worry about somatic symptoms as a sign of cancer recurrence: prevalence and associations with fear of recurrence and quality of life in survivors of childhood cancer.

OBJECTIVE: Somatic symptoms (e.g., pain, fatigue) are common after childhood cancer and are associated with greater fear of cancer recurrence and poorer health-related quality of life (HRQoL). Qualitative studies indicate that survivors of childhood cancer (SCCs) worry about somatic symptoms as indicating cancer recurrence, which could in part explain associations between symptoms and poorer psychosocial outcomes. However, the prevalence, characteristics, and impact of symptom worry has not been quantitatively studied. METHODS: SCCs (N = 111; 52% female; Mage at study = 17.67 years, range = 8-25 years; Mage at diagnosis = 6.70 years) across a variety of diagnoses were recruited from a pediatric cancer center in Canada and completed self-report measures of symptom worry, symptom frequency, general anxiety, fear of cancer recurrence, and HRQoL. RESULTS: A majority (62%) of SCCs worried about at least one symptom as a sign of recurrence. Pain was the most worrisome symptom, but SCCs also reported worrying about symptoms that are rarely associated with cancer recurrence such as hunger, dizziness, and feeling cold. Symptom worry was more strongly associated with fear of cancer recurrence than the mere frequency of those symptoms, and this relationship held while controlling for treatment factors and general anxiety. Symptom worry and frequency each explained unique variance in HRQoL. CONCLUSIONS: Worry about somatic symptoms as a sign of cancer recurrence is common and may be impactful after childhood cancer. Excessive worry about somatic symptoms could be an important target to reduce fear of recurrence and increase HRQoL in SCCs.

Experimental research in environmentally induced hyperthermic older persons: A systematic quantitative literature review mapping the available evidence.

The heat-related health burden is expected to persist and worsen in the coming years due to an aging global population and climate change. Defining the breadth and depth of our understanding of age-related changes in thermoregulation can identify underlying causes and strategies to protect vulnerable individuals from heat. We conducted the first systematic quantitative literature review to provide context to the historical experimental research of healthy older adults - compared to younger adults or unhealthy age matched cases - during exogenous heat strain, focusing on factors that influence thermoregulatory function (e.g. co-morbidities). We identified 4,455 articles, with 147 meeting eligibility criteria. Most studies were conducted in the US (39%), Canada (29%), or Japan (12%), with 71% of the 3,411 participants being male. About 71% of the studies compared younger and older adults, while 34% compared two groups of older adults with and without factors influencing thermoregulation. Key factors included age combined with another factor (23%), underlying biological mechanisms (18%), age independently (15%), influencing health conditions (15%), adaptation potential (12%), environmental conditions (9%), and therapeutic/pharmacological interventions (7%). Our results suggest that controlled experimental research should focus on the age-related changes in thermoregulation in the very old, females, those with overlooked chronic heat-sensitive health conditions (e.g. pulmonary, renal, mental disorders), the impact of multimorbidity, prolonged and cumulative effects of extreme heat, evidence-based policy of control measures (e.g. personal cooling strategies), pharmaceutical interactions, and interventions stimulating protective physiological adaptation. These controlled studies will inform the directions and use of limited resources in ecologically valid fieldwork studies.

International Survey of Pediatric Oncologists' Beliefs and Communication Practices Regarding Symptom Self-Monitoring by Childhood Cancer Survivors.

PURPOSE: Childhood cancer survivors report self-monitoring for and worrying about symptoms of disease recurrence and secondary cancers, although symptom-related worry is associated with poorer health-related quality of life. This survey captured pediatric oncologists' beliefs and communication practices regarding symptom self-monitoring for childhood cancer survivors. METHODS: Using a closed-loop snowball sampling technique, pediatric oncologists completed an online survey regarding the importance of symptom self-monitoring for off-therapy patients, the degree to which symptom self-monitoring was perceived to cause stress and worry, and communication practices. RESULTS: 196 pediatric oncologists (White [78%]; female [64%]; Mage = 47 years) from every continent except Antarctica participated. Oncologists believed it is important for off-therapy patients to self-monitor for symptoms of cancer recurrence (90%) and treatment late effects (94%), although some noted that recurrence (30%) and late effects (55%) are typically detected by routine surveillance before symptoms appear. Oncologists varied in their beliefs that off-therapy patients do (31%) or do not (31%) worry unnecessarily about symptoms of recurrence. Two thirds (62%) of oncologists reported often/always discussing with off-therapy patients which symptoms could indicate cancer recurrence, whereas fewer than half (43%) often/always discussed which symptoms were unlikely to indicate recurrence. Oncologists identified a need for education regarding how to communicate around symptom self-monitoring and the potential utility of a screening tool to identify those who worry excessively. CONCLUSION: Despite nearly universal belief that their off-therapy patients should self-monitor for symptoms of disease recurrence and late effects, a substantial proportion of pediatric oncologists do not counsel patients on symptom self-monitoring. Since nearly one-third believe that off-therapy patients worry unnecessarily about symptoms of recurrence, improving patient education regarding which symptoms are and are not medically concerning could decrease stress and improve health-related quality of life for pediatric cancer survivors.

Unique associations of pain frequency and pain-related worry with health-related quality of life in survivors of childhood cancer.

Introduction: Pain is common during childhood cancer treatment, can persist into survivorship, and can negatively affect health-related quality of life in survivors of childhood cancers (SCCs). Objective: The objective of this brief report was to assess pain frequency, pain-related worry, and their (unique) associations with health-related quality of life in SCCs. Methods: One hundred eleven SCCs (52% female individuals, M age: 17.67 years, range 8-25 years) completed self-report measures of pain frequency, pain-related worry, and health-related quality of life. Results: More than two-thirds (70%) of SCCs reported pain in the previous month (M = 1.39, SD = 1.17), and 15% reported experiencing pain often or almost always. More than one-third (39%) reported worrying about pain as a sign of cancer recurrence (M = 0.73, SD = 1.07), and 9% reported worrying about pain a lot or a whole lot. In multivariate regression models that controlled for sex, age at diagnosis, and time off treatment, both pain frequency and pain-related worry were significantly associated with physical health-related quality of life, indicating that they contribute unique variance to health-related quality of life after childhood cancer. For emotional health-related quality of life, pain frequency was no longer a significant predictor once pain-related worry was added to the model, indicating that pain-related worry may be particularly important for understanding emotional health-related quality of life. Conclusion: Postcancer pain may contribute to health-related quality of life through multiple mechanisms, including by triggering concerns of recurrence. There is a need for clinical interventions that target both the frequency of pain (eg, behavioral interventions) and pain-related worry (eg, psychoeducation and cognitive interventions) to improve health-related quality of life after childhood cancer.

Functional Genomics of Healthy and Pathological Fetal Membranes.

Premature preterm rupture of membranes (PPROM), rupture of fetal membranes before 37 weeks of gestation, is the leading identifiable cause of spontaneous preterm births. Often there is no obvious cause that is identified in a patient who presents with PPROM. Identifying the upstream molecular events that lead to fetal membrane weakening presents potentially actionable mechanisms which could lead to the identification of at-risk patients and to the development of new therapeutic interventions. Functional genomic studies have transformed understanding of the role of gene regulation in diverse cells and tissues involved health and disease. Here, we review the results of those studies in the context of fetal membranes. We will highlight relevant results from major coordinated functional genomics efforts and from targeted studies focused on individual cell or tissue models. Studies comparing gene expression and DNA methylation between healthy and pathological fetal membranes have found differential regulation between labor and quiescent tissue as well as in preterm births, preeclampsia, and recurrent pregnancy loss. Whole genome and exome sequencing studies have identified common and rare fetal variants associated with preterm births. However, few fetal membrane tissue studies have modeled the response to stimuli relevant to pregnancy. Fetal membranes are readily adaptable to cell culture and relevant cellular phenotypes are readily observable. For these reasons, this is now an unrealized opportunity for genomic studies isolating the effect of cell signaling cascades and mapping the fetal membrane responses that lead to PPROM and other pregnancy complications.