Bronchial cell epigenetic aging in a human experimental study of short-term diesel and ozone exposures.

Blood-based, observational, and cross-sectional epidemiological studies suggest that air pollutant exposures alter biological aging. In a single-blinded randomized crossover human experiment of 17 volunteers, we examined the effect of randomized 2-h controlled air pollution exposures on respiratory tissue epigenetic aging. Bronchial epithelial cell DNA methylation 24 h post-exposure was measured using the HumanMethylation450K BeadChip, and there was a minimum 2-week washout period between exposures. All 17 volunteers were exposed to ozone, but only 13 were exposed to diesel exhaust. Horvath DNAmAge [Pearson coefficient (r) = 0.64; median absolute error (MAE) = 2.7 years], GrimAge (r = 0.81; MAE = 13 years), and DNAm Telomere Length (DNAmTL) (r = -0.65) were strongly correlated with chronological age in this tissue. Compared to clean air, ozone exposure was associated with longer DNAmTL (median difference 0.11 kb, Fisher's exact P-value = .036). This randomized trial suggests a weak relationship of ozone exposure with DNAmTL in target respiratory cells. Still, causal relationships with long-term exposures need to be evaluated.

County-level associations between drinking water PFAS contamination and COVID-19 mortality in the United States.

BACKGROUND: Epidemiologic and animal studies both support relationships between exposures to per- and polyfluoroalkyl substances (PFAS) and harmful effects on the immune system. Accordingly, PFAS have been identified as potential environmental risk factors for adverse COVID-19 outcomes. OBJECTIVE: Here, we examine associations between PFAS contamination of U.S. community water systems (CWS) and county-level COVID-19 mortality records. Our analyses leverage two datasets: one at the subnational scale (5371 CWS serving 621 counties) and one at the national scale (4798 CWS serving 1677 counties). The subnational monitoring dataset was obtained from statewide drinking monitoring of PFAS (2016-2020) and the national monitoring dataset was obtained from a survey of unregulated contaminants (2013-2015). METHODS: We conducted parallel analyses using multilevel quasi-Poisson regressions to estimate cumulative incidence ratios for the association between county-level measures of PFAS drinking water contamination and COVID-19 mortality prior to vaccination onset (Jan-Dec 2020). In the primary analyses, these regressions were adjusted for several county-level sociodemographic factors, days after the first reported case in the county, and total hospital beds. RESULTS: In the subnational analysis, detection of at least one PFAS over 5 ng/L was associated with 12% higher [95% CI: 4%, 19%] COVID-19 mortality. In the national analysis, detection of at least one PFAS above the reporting limits (20-90 ng/L) was associated with 13% higher [95% CI: 8%, 19%] COVID-19 mortality. IMPACT STATEMENT: Our findings provide evidence for an association between area-level drinking water PFAS contamination and higher COVID-19 mortality in the United States. These findings reinforce the importance of ongoing state and federal monitoring efforts supporting the U.S. Environmental Protection Agency's 2024 drinking water regulations for PFAS. More broadly, this example suggests that drinking water quality could play a role in infectious disease severity. Future research would benefit from study designs that combine area-level exposure measures with individual-level outcome data.

Accelerated aging and altered subclinical response to ozone exposure in young, healthy adults.

Ozone exposure induces a myriad of adverse cardiopulmonary outcomes in humans. Although advanced age and chronic disease are factors that may exacerbate a person's negative response to ozone exposure, there are no molecular biomarkers of susceptibility. Here, we examine whether epigenetic age acceleration (EAA) is associated with responsiveness to short-term ozone exposure. Using data from a crossover-controlled exposure study (n = 17), we examined whether EAA, as measured in lung epithelial cells collected 24 h after clean air exposure, modifies the observed effect of ozone on autonomic function, cardiac electrophysiology, hemostasis, pulmonary function, and inflammation. EAA was assessed in lung epithelial cells extracted from bronchoalveolar lavage fluids, using the pan-tissue aging clock. We used two analytic approaches: (i) median regression to estimate the association between EAA and the estimated risk difference for subclinical responses to ozone and (ii) a block randomization approach to estimate EAA's effect modification of subclinical responses. For both approaches, we calculated Fisher-exact P-values, allowing us to bypass large sample size assumptions. In median regression analyses, accelerated epigenetic age modified associations between ozone and heart rate-corrected QT interval (QTc) ([Formula: see text]= 0.12, P-value = 0.007) and between ozone and C-reactive protein ([Formula: see text] = -0.18, P = 0.069). During block randomization, the directions of association remained consistent for QTc and C-reactive protein; however, the P-values weakened. Block randomization also revealed that responsiveness of plasminogen activator inhibitor-1 (PAI-1) to ozone exposure was modified by accelerated epigenetic aging (PAI-1 difference between accelerated aging-defined block groups = -0.54, P-value = 0.039). In conclusion, EAA is a potential biomarker for individuals with increased susceptibility to ozone exposure even among young, healthy adults.

Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design.

IMPORTANCE: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. OBSERVATIONS: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. CONCLUSIONS AND RELEVANCE: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

Researching COVID to enhance recovery (RECOVER) tissue pathology study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) tissue pathology study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository. METHODS: RECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Causal inference methods will be employed to investigate associations between risk factors and pathologic outcomes. DISCUSSION: RECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC.

A permutation-based approach using a rank-based statistic to identify sex differences in epigenetics.

Epigenetic sex differences and their resulting implications for human health have been studied for about a decade. The objective of this paper is to use permutation-based inference and a new ranked-based test statistic to identify sex-based epigenetic differences in the human DNA methylome. In particular, we examine whether we could identify separations between the female and male distributions of DNA methylation across hundred of thousands CpG sites in two independent cohorts, the Swedish Adoption Twin study and the Lamarck study. Based on Fisherian p-values, we set a threshold for methylation differences "worth further scrutiny". At this threshold, we were able to confirm previously-found CpG sites that stratify with respect to sex. These CpG sites with sex differences in DNA methylation should be further investigated for their possible contribution to various physiological and pathological functions in the human body. We followed-up our statistical analyses with a literature review in order to inform the proposed disease implications for the loci we uncovered.

Targeting emotional regulation using an Internet-delivered psychological intervention for cancer survivors: A randomized controlled trial.

OBJECTIVES: This trial assessed the efficacy of an emotion-focused, modular, Internet-delivered adaptation of the Unified Protocol (UP) in improving cancer survivors' emotion regulation strategies. DESIGN: A two-arm randomized controlled trial (1:1) was used to compare the efficacy of two Internet-based interventions: UP-adapted CanCope Mind (CM) and lifestyle-focused active control CanCope Lifestyle (CL). METHODS: N = 224 cancer survivors randomized to CM or CL were assessed at baseline, between-modules, at post-intervention and 3-month follow-up on emotion regulation outcomes targeted by each CM module (Module 1: beliefs about emotions; Module 2: mindfulness; Module 3: cognitive reappraisal skills, catastrophizing, refocus on planning; Module 4: experiential avoidance). Primary analyses were intention-to-treat linear regressions using Fisher randomization tests for p-values and intervals were used to compare groups with standardized mean difference (SMD) effect sizes. RESULTS: CanCope Mind participants (n = 61 completers) experienced moderate-to-large improvements (SMDs from .44-.88) across all outcomes at post-intervention. CM's effects were larger than CL's (n = 75 completers) immediately post-intervention and at 3-month follow-up for beliefs about emotions, mindfulness, cognitive reappraisals and experiential avoidance (all p's < .05). CM experienced greater improvements in catastrophizing immediately post-intervention, with a trending effect at follow-up. However, we could not reject the null hypothesis of identical between-group effects for refocusing on planning both immediately post-intervention and at follow-up. Exploratory analyses revealed inconsistent between-module effects. CONCLUSIONS: In its entirety, CM is a promising intervention for improving and maintaining cancer survivors' adaptive emotion regulation, especially for mindfulness and experiential avoidance. This may have important clinical implications for promoting cancer survivors' emotional functioning and general well-being.

The natural history of ALS: Baseline characteristics from a multicenter clinical cohort.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare disease with urgent need for improved treatment. Despite the acceleration of research in recent years, there is a need to understand the full natural history of the disease. As only 40% of people living with ALS are eligible for typical clinical trials, clinical trial datasets may not generalize to the full ALS population. While biomarker and cohort studies have more generous inclusion criteria, these too may not represent the full range of phenotypes, particularly if the burden for participation is high. To permit a complete understanding of the heterogeneity of ALS, comprehensive data on the full range of people with ALS is needed. METHODS: The ALS Natural History Consortium (ALS NHC) consists of nine ALS clinics and was created to build a comprehensive dataset reflective of the ALS population. At each clinic, most patients are asked to participate and about 95% do. After obtaining consent, a minimum dataset is abstracted from each participant's electronic health record. Participant burden is therefore minimal. RESULTS: Data on 1925 ALS patients were submitted as of 9 December 2022. ALS NHC participants were more heterogeneous relative to anonymized clinical trial data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The ALS NHC includes ALS patients of older age of onset and a broader distribution of El Escorial categories, than the PRO-ACT database. CONCLUSIONS: ALS NHC participants had a higher diversity of diagnostic and demographic data compared to ALS clinical trial participants.Key MessagesWhat is already known on this topic: Current knowledge of the natural history of ALS derives largely from regional and national registries that have broad representation of the population of people living with ALS but do not always collect covariates and clinical outcomes. Clinical studies with rich datasets of participant characteristics and validated clinical outcomes have stricter inclusion and exclusion criteria that may not be generalizable to the full ALS population.What this study adds: To bridge this gap, we collected baseline characteristics for a sample of the population of people living with ALS seen at a consortium of ALS clinics that collect extensive, pre-specified participant-level data, including validated outcome measures.How this study might affect research, practice, or policy: A clinic-based longitudinal dataset can improve our understanding of the natural history of ALS and can be used to inform the design and analysis of clinical trials and health economics studies, to help the prediction of clinical course, to find matched controls for open label extension trials and expanded access protocols, and to document real-world evidence of the impact of novel treatments and changes in care practice.

The role of combat exposure on drinking behavior and subjective well-being: A Rubin Causal Model approach.

OBJECTIVE: Investigating the role of combat exposure on behavioral outcomes has been limited due to ethical and logistical constraints. METHOD: Using a large data set from UK BioBank of U.K. citizens (n = 157,161), we created hypothetical randomized experiments, with treatment conditions for combat exposure or no combat exposure matched for relevant covariates and compared differences in combat exposure groups on a broad range of alcohol-related and subjective well-being outcomes. Additionally, using a randomization-based approach, we calculated 95% Fisherian intervals for constant treatment effects consistent with the matched data and the hypothetical combat exposure intervention. RESULTS: Results suggest that combat exposure plays a role in several negative outcomes related to alcohol behavior and subjective well-being, such as increased typical daily alcohol consumption (estimated average causal effect [ACE] = 0.0545, Fisher p-value = .0119) and less general health happiness (estimated ACE = -0.1077, Fisher p-value < 1/100,000). CONCLUSIONS: This study expands our current understanding of the role of combat exposure on many alcohol and subjective well-being-related measures. We also show that the Rubin Causal Model provides a rigorous and valid approach to better understand myriad other issues in psychological science. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection.

Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds). Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. METHODS: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. DISCUSSION: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options. REGISTRATION: NCT05172024.

Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design.

Importance: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. Observations: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's RE searching COV ID to E nhance R ecovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of five cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study ( n =10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n=6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n=6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n=600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. Conclusions and Relevance: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. Clinical Trialsgov Identifier: Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT05172011.

Researching COVID to enhance recovery (RECOVER) pregnancy study: Rationale, objectives and design.

Importance: Pregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER- Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads. Methods: RECOVER-Pregnancy cohort is a combined prospective and retrospective cohort that proposes to enroll 2,300 individuals with a pregnancy during the COVID-19 pandemic and their offspring exposed and unexposed in utero, including single and multiple gestations. Enrollment will occur both in person at 27 sites through the Eunice Kennedy Shriver National Institutes of Health Maternal-Fetal Medicine Units Network and remotely through national recruitment by the study team at the University of California San Francisco (UCSF). Adults with and without SARS-CoV-2 infection during pregnancy are eligible for enrollment in the pregnancy cohort and will follow the protocol for RECOVER-Adult including validated screening tools, laboratory analyses and symptom questionnaires followed by more in-depth phenotyping of PASC on a subset of the overall cohort. Offspring exposed and unexposed in utero to SARS-CoV-2 maternal infection will undergo screening tests for neurodevelopment and other health outcomes at 12, 18, 24, 36 and 48 months of age. Blood specimens will be collected at 24 months of age for SARS-CoV-2 antibody testing, storage and anticipated later analyses proposed by RECOVER and other investigators. Discussion: RECOVER-Pregnancy will address whether having SARS-CoV-2 during pregnancy modifies the risk factors, prevalence, and phenotype of PASC. The pregnancy cohort will also establish whether there are increased risks of adverse long-term outcomes among children exposed in utero. Registration: NCT05172024.

High-dimensional randomization-based inference capitalizing on classical design and modern computing.

A common complication that can arise with analyses of high-dimensional data is the repeated use of hypothesis tests. A second complication, especially with small samples, is the reliance on asymptotic p-values. Our proposed approach for addressing both complications uses a scientifically motivated scalar summary statistic, and although not entirely novel, seems rarely used. The method is illustrated using a crossover study of seventeen participants examining the effect of exposure to ozone versus clean air on the DNA methylome, where the multivariate outcome involved 484,531 genomic locations. Our proposed test yields a single null randomization distribution, and thus a single Fisher-exact p-value that is statistically valid whatever the structure of the data. However, the relevance and power of the resultant test requires the careful a priori selection of a single test statistic. The common practice using asymptotic p-values or meaningless thresholds for "significance" is inapposite in general.

Assessing an Internet-Delivered, Emotion-Focused Intervention Compared With a Healthy Lifestyle Active Control Intervention in Improving Mental Health in Cancer Survivors: Protocol for a Randomized Controlled Trial.

BACKGROUND: Cancer survivors are vulnerable to experiencing symptoms of anxiety and depression and may benefit from accessible interventions focused on improving emotion regulation. CanCope Mind (CM) was developed as an internet-delivered intervention adapted from the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders to improve emotion regulation and support the mental health of cancer survivors. OBJECTIVE: This protocol aims to provide an outline of the CanCope Study, a trial comparing the efficacy of a Unified Protocol-adapted internet-delivered intervention (CM) designed for cancer survivors compared with an active control condition-an internet-delivered healthy lifestyle intervention, CanCope Lifestyle (CL). The primary aim is to assess and compare the efficacy of both interventions in improving emotion regulation, anxiety and depressive symptoms, and quality of life. The secondary aims involve assessing the mechanisms of the CM intervention. METHODS: This trial is a 2-arm randomized controlled trial that allocates cancer survivors to either CM or CL. Both interventions comprise 4 web-based modules and are expected to take participants at least 8 weeks to complete. Participants' mental and physical health will be assessed via self-reported surveys at baseline (T0), between each module (T1, T2, and T3), immediately after the intervention (T4), and at 3-month follow-up (T5). The study aims to recruit 110 participants who have completed T4. RESULTS: The CanCope study began recruitment in September 2020. A total of 224 participants have been randomized to the CM (n=110, 49.1%) and CL (n=114, 50.9%) groups. CONCLUSIONS: This is one of the first trials to develop and investigate the efficacy of a web-based intervention for cancer survivors that specifically targets emotion regulation. TRIAL REGISTRATION: Australian Clinical Trials ACTRN12620000943943; https://tinyurl.com/b3z9cjsp. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36658.

A randomization-based causal inference framework for uncovering environmental exposure effects on human gut microbiota.

Statistical analysis of microbial genomic data within epidemiological cohort studies holds the promise to assess the influence of environmental exposures on both the host and the host-associated microbiome. However, the observational character of prospective cohort data and the intricate characteristics of microbiome data make it challenging to discover causal associations between environment and microbiome. Here, we introduce a causal inference framework based on the Rubin Causal Model that can help scientists to investigate such environment-host microbiome relationships, to capitalize on existing, possibly powerful, test statistics, and test plausible sharp null hypotheses. Using data from the German KORA cohort study, we illustrate our framework by designing two hypothetical randomized experiments with interventions of (i) air pollution reduction and (ii) smoking prevention. We study the effects of these interventions on the human gut microbiome by testing shifts in microbial diversity, changes in individual microbial abundances, and microbial network wiring between groups of matched subjects via randomization-based inference. In the smoking prevention scenario, we identify a small interconnected group of taxa worth further scrutiny, including Christensenellaceae and Ruminococcaceae genera, that have been previously associated with blood metabolite changes. These findings demonstrate that our framework may uncover potentially causal links between environmental exposure and the gut microbiome from observational data. We anticipate the present statistical framework to be a good starting point for further discoveries on the role of the gut microbiome in environmental health.

The role of body mass index at diagnosis of colorectal cancer on Black-White disparities in survival: a density regression mediation approach.

The study of racial/ethnic inequalities in health is important to reduce the uneven burden of disease. In the case of colorectal cancer (CRC), disparities in survival among non-Hispanic Whites and Blacks are well documented, and mechanisms leading to these disparities need to be studied formally. It has also been established that body mass index (BMI) is a risk factor for developing CRC, and recent literature shows BMI at diagnosis of CRC is associated with survival. Since BMI varies by racial/ethnic group, a question that arises is whether differences in BMI are partially responsible for observed racial/ethnic disparities in survival for CRC patients. This article presents new methodology to quantify the impact of the hypothetical intervention that matches the BMI distribution in the Black population to a potentially complex distributional form observed in the White population on racial/ethnic disparities in survival. Our density mediation approach can be utilized to estimate natural direct and indirect effects in the general causal mediation setting under stronger assumptions. We perform a simulation study that shows our proposed Bayesian density regression approach performs as well as or better than current methodology allowing for a shift in the mean of the distribution only, and that standard practice of categorizing BMI leads to large biases when BMI is a mediator variable. When applied to motivating data from the Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium, our approach suggests the proposed intervention is potentially beneficial for elderly and low-income Black patients, yet harmful for young or high-income Black populations.

The role of family history of Cancer in Oral Cavity Cancer.

OBJECTIVES: Oral and oropharyngeal squamous cell carcinoma (SCC) is the 10th most common cancer in the United States (8th in males, 13th in females), with an estimated 54,010 new cases expected in 2021, and is primarily associated with smoked tobacco, heavy alcohol consumption, areca nut use and persistent high-risk human papillomavirus (HPV). Family history of cancer (FHC) and family history of head and neck cancer (FHHNC) have been reported to play an important role in the development of OSCC. We aimed to investigate the role of FHC, FHHNC and personal history of cancer in first/second degree-relatives as co-risk factors for oral cancer. METHODS: This was a retrospective study of patients diagnosed with OSCC at the Division of Oral Medicine and Dentistry at Brigham and Women's Hospital and at the Division of Head and Neck Oncology at Dana Farber Cancer Institute. Conditional logistic regressions were performed to examine whether OSCC was associated with FHC and FHHNC of FDRs and SDRs, personal history of cancer and secondary risk factors. RESULTS: Overall, we did not find an association between FHC, FHHNC and OSCC risk, whereas patients with a cancer history in one of their siblings were 1.6-times more likely to present with an OSCC. When secondary risk factors were considered, patients with a history of oral leukoplakia and dysplasia had a 16-times higher risk of having an OSCC. CONCLUSIONS: Our study confirmed that a previous history of oral leukoplakia or dysplasia was an independent risk factor for OSCC. A positive family history of cancer in one or more siblings may be an additional risk factor for OSCC.

Collective behavior emerges from genetically controlled simple behavioral motifs in zebrafish.

It is not understood how changes in the genetic makeup of individuals alter the behavior of groups of animals. Here, we find that, even at early larval stages, zebrafish regulate their proximity and alignment with each other. Two simple visual responses, one that measures relative visual field occupancy and one that accounts for global visual motion, suffice to account for the group behavior that emerges. Mutations in genes known to affect social behavior in humans perturb these simple reflexes in individual larval zebrafish and change their emergent collective behaviors in the predicted fashion. Model simulations show that changes in these two responses in individual mutant animals predict well the distinctive collective patterns that emerge in a group. Hence, group behaviors reflect in part genetically defined primitive sensorimotor "motifs," which are evident even in young larvae.

Multiple sclerosis incidence rate in southern Iran: a Bayesian epidemiological study.

BACKGROUND: Multiple Sclerosis (MS) remains to be a public health challenge, due to its unknown biological mechanisms and clinical impacts on young people. The prevalence of this disease in Iran is reported to be 5.30 to 74.28 per 100,000-person. Because of high prevalence of this disease in Fars province, the purpose of this study was to assess the spatial pattern of MS incidence rate by modeling both the associations s of spatial dependence between neighboring regions and risk factors in a Bayesian Poisson model, which can lead to the improvement of health resource allocation decisions. METHOD: Data from 5468 patients diagnosed with MS were collected, according to the McDonald's criteria. New cases of MS were reported by the MS Society of Fars province from 1991 until 2016. The association between the percentage of people with low vitamin D intake, smoking, abnormal BMI and alcohol consumption in addition to spatial structure in a Bayesian spatio-temporal hierarchical model were used to determine the relative risk and trend of MS incidence rate in 29 counties of Fars province. RESULTS: County-level crude incidence rates ranged from 0.22 to 11.31 cases per 100,000-person population. The highest relative risk was estimated at 1.80 in the county of Shiraz, the capital of Fars province, while the lowest relative risk was estimated at 0.11 in Zarindasht county in southern of Fars. The percentages of vitamin D supplementation intake and smoking were significantly associated with the incidence rate of MS. The results showed that 1% increase in vitamin D supplementation intake is associated with 2% decrease in the risk of MS and 1% increase in smoking is associated with 16% increase in the risk of MS. CONCLUSION: Bayesian spatio-temporal analysis of MS incidence rate revealed that the trend in the south and south east of Fars province is less steep than the mean trend of this disease. The lower incidence rate was associated with a higher percentage of vitamin D supplementation intake and a lower percentage of smoking. Previous studies have also shown that smoking and low vitamin D, among all covariates or risk factors, might be associated with high incidence of MS.