Cell lineage analysis with somatic mutations reveals late divergence of neuronal cell types and cortical areas in human cerebral cortex.

The mammalian cerebral cortex shows functional specialization into regions with distinct neuronal compositions, most strikingly in the human brain, but little is known in about how cellular lineages shape cortical regional variation and neuronal cell types during development. Here, we use somatic single nucleotide variants (sSNVs) to map lineages of neuronal sub-types and cortical regions. Early-occurring sSNVs rarely respect Brodmann area (BA) borders, while late-occurring sSNVs mark neuron-generating clones with modest regional restriction, though descendants often dispersed into neighboring BAs. Nevertheless, in visual cortex, BA17 contains 30-70% more sSNVs compared to the neighboring BA18, with clones across the BA17/18 border distributed asymmetrically and thus displaying different cortex-wide dispersion patterns. Moreover, we find that excitatory neuron-generating clones with modest regional restriction consistently share low-mosaic sSNVs with some inhibitory neurons, suggesting significant co-generation of excitatory and some inhibitory neurons in the dorsal cortex. Our analysis reveals human-specific cortical cell lineage patterns, with both regional inhomogeneities in progenitor proliferation and late divergence of excitatory/inhibitory lineages.

An Adaptive, Algorithm-based Text Message Intervention to Promote Health Behavior Adherence in Type 2 Diabetes: Treatment Development and Proof-of-Concept Trial.

BACKGROUND: Most individuals with type 2 diabetes (T2D) struggle to adhere to one or more health behaviors. Text message interventions (TMIs) have the potential to improve adherence but have had mixed effects on diet and activity in T2D. We developed an eight-week, adaptive, algorithm-driven TMI to promote physical activity, diet, self-care, and well-being. Then, in a single-arm trial, we assessed its feasibility, acceptability, and preliminary efficacy in 15 individuals with T2D and suboptimal adherence. METHODS: Participants received daily text messages and were asked to rate the utility of each message (0=not helpful, 10=very helpful). These ratings were used by an algorithm to select subsequent messages based on each participant's prior ratings. We assessed intervention feasibility by rates of message transmission/response and acceptability through ratings of message utility and burden. Finally, we examined pre-post changes in diabetes self-care, diet, physical activity, and psychological outcomes and calculated effect sizes (Cohen's d). RESULTS: All text messages were delivered, and participants provided ratings for 79% of messages, above our a priori thresholds for feasibility. Participants rated the individual messages and overall TMI as subjectively useful (utility: 8.1 [SD=2.1] and 7.8 [SD=2.0], respectively) and not burdensome (burden: 0.8 [SD=1.8]). The intervention led to significant, medium- to large-sized improvements in self-care (d=0.77), diet (d=0.99), and activity (d=0.61) but minimal change in psychological outcomes. CONCLUSIONS: The TMI was feasible and well-accepted, and it led to promising improvements in adherence-related outcomes. These findings should be confirmed in a larger randomized controlled trial.

Association between SARS-CoV-2 infection during pregnancy and postpartum depressive and anxiety symptoms: finding from the International Registry of Coronavirus Exposure in Pregnancy (IRCEP) study.

While there has been concern over the perinatal mental health implications of the COVID-19 outbreak, evidence on the risk of postpartum depression and anxiety following SARS-CoV-2 infection is limited. We studied this question using the International Registry of Coronavirus Exposure in Pregnancy, which included both a prospective and retrospective cohort. Study participants were required to have been tested for SARS-CoV-2 between the date of last menstrual period and delivery. The exposure of interest was SARS-CoV-2 infection during pregnancy, as well as COVID-19 severity (severe, moderate, mild, and asymptomatic). The outcome was postpartum depression and anxiety symptoms, assessed by the 4-item Patient Health Questionnaire. The final analytic cohort consisted of 3819 participants (COVID-19 positive: 771; COVID-19 negative: 3048). After adjusting for confounding by socio-demographics, prior obstetric and maternal health comorbidities, mothers with severe COVID-19 had an increased risk of depressive (aRR: 1.72; 95%CI: 1.18-2.52) and anxiety (aRR: 1.40; 0.98-2.00) symptoms. The strength of the association was attenuated for women with moderate COVID-19 (aRR = 1.12; 0.86-1.44 for depressive symptoms; aRR = 1.18; 0.96-1.44 for anxiety symptoms). No increased risk was observed for mild or asymptomatic illness. The findings can inform targeted interventions to minimize the risk of adverse COVID-19-related mental health outcomes for pregnant women.

A Care Management Intervention for Noncardiac Chest Pain: Treatment Development and Feasibility Assessment.

ABSTRACT.Objective: Noncardiac chest pain is common and can cause distress, impair quality of life, and lead to recurrent evaluation. It is often multifactorial in etiology and influenced by psychological factors. The objective of this study was to describe the development, implementation, and preliminary feasibility of an 8-week multicomponent care management intervention.Methods: Participants with noncardiac chest pain were recruited from primary care clinics, ambulatory cardiac stress testing, and the emergency department (ED) at an urban academic hospital from March 2019 to November 2019. The care management team consisted of a nurse, cardiologist, and psychiatrist. Following a 1-time consultation visit with the cardiologist and nurse, evaluation and treatment recommendations were conveyed to the participant's primary care physician. The nurse completed 8 weekly phone calls with the participant to provide support, introduce therapeutic principles, and assist with care coordination under the supervision of a psychiatrist. Intervention feasibility was assessed on 7 domains. To examine preliminary efficacy, the number of ED visits was recorded, and participants completed pre-post measures of psychological health and health-related quality of life and Likert scales of chest pain symptom severity, frequency, and impact.Results: The intervention was developed and implemented in 3 patients who completed 100% of the consultation visits and a mean of 95.8% of study phone calls. There were no adverse events or ED visits. Mean scores for chest pain severity, chest pain frequency, chest pain impact, depression, anxiety, and somatization all improved. No other trends were observed.Conclusions: The findings suggest that a care management intervention may be feasible with potential to improve chest pain symptoms and psychological outcomes. A larger, randomized trial is needed to explore the efficacy of this intervention.Trial Registration: ClinicalTrials.gov identifier: NCT04904198.

The role of positive psychological constructs in diet and eating behavior among people with metabolic syndrome: A qualitative study.

Positive Psychological (PP) constructs (e.g., optimism and gratitude) may impact the adherence to healthy behaviors, including diet, though prior studies have shown mixed findings. This qualitative study explored the relationships between PP constructs and dietary behaviors among 21 adults with metabolic syndrome through semi-structured interviews. Directed content analysis led to five themes: eating healthfully leads to PP constructs, PP constructs lead to eating healthfully, eating healthfully prevents negative emotions, healthy behaviors associated with diet, and an upward healthy spiral. Given the close relationship between PP constructs and diet, these may be targeted to improve diet in risk populations through interventions that promote well-being.

An Adaptive Text Message Intervention to Promote Well-Being and Health Behavior Adherence for Patients With Cardiovascular Disease: Intervention Design and Preliminary Results.

BACKGROUND: Most individuals with heart disease struggle to adhere to cardiovascular health behaviors, despite their known health benefits. Text message interventions (TMIs) are a promising treatment modality for health behavior promotion, but existing TMIs typically deliver a fixed set of messages and do not target well-being constructs associated with adherence and cardiovascular health. OBJECTIVE: To develop a 4-week TMI, which delivers daily messages to promote well-being and adherence to health behaviors and dynamically adapts based on participant feedback to deliver increasingly customized messages; and to assess its feasibility, acceptability, and preliminary efficacy in a single-arm, proof-of-concept trial in 14 individuals with coronary artery disease (age mean = 67.9, standard deviation = 8.7). METHODS: Participants received daily text messages related to well-being, physical activity, or diet, rated each message's utility, and these ratings informed the TMI's choice of future text messages. Feasibility was assessed by the proportion of messages successfully sent, and acceptability was assessed by participant ratings of intervention burden and text message utility. Finally, the intervention's preliminary efficacy was explored by measuring pre-post changes in psychologic and behavioral outcomes. RESULTS: The TMI was both feasible (93% of participants received all messages) and well-accepted (mean text message utility: 7.0 of 10 [standard deviation 2.5]; mean intervention utility: 6.4 of 10 [standard deviation 0.9]; mean intervention burden: 0.5 of 10 [standard deviation 0.9]). Participants reported that messages related to well-being were particularly helpful and that most messages led to an action (e.g., eating more vegetables, being kind to others). The TMI led to nonsignificant, small-to-medium effect size improvements in happiness, optimism, determination, depression, anxiety, self-rated health, and diet (d = 0.19-0.48), and, unexpectedly, small reductions in activity and physical function (d = -0.20 and -0.32). CONCLUSIONS: The adaptive TMI was feasible, well-accepted, and associated with nonsignificant improvements in psychologic outcomes and mixed effects on behavioral outcomes. Larger, well-powered studies are needed to determine whether this TMI will be able to improve well-being and health-related outcomes in this high-risk population.

Feelings of Culpability: Just Following Orders Versus Making the Decision Oneself.

In five experiments (N = 1,490), participants were asked to imagine themselves as programmers of self-driving cars who had to decide how to program the car to respond in a potential accident: spare the driver or spare pedestrians. Alternatively, participants imagined that they were a mayor grappling with difficult moral dilemmas concerning COVID-19. Either they, themselves, had to decide how to program the car or which COVID-19 policy to implement (high-agency condition) or they were told by their superior how to act (low-agency condition). After learning that a tragic outcome occurred because of their action, participants reported their felt culpability. Although we expected people to feel less culpable about the outcome if they acted in accordance with their superior's injunction than if they made the decision themselves, participants actually felt more culpable when they followed their superior's order. Some possible reasons for this counterintuitive finding are discussed.

Landmarks of human embryonic development inscribed in somatic mutations.

Although cell lineage information is fundamental to understanding organismal development, very little direct information is available for humans. We performed high-depth (250×) whole-genome sequencing of multiple tissues from three individuals to identify hundreds of somatic single-nucleotide variants (sSNVs). Using these variants as "endogenous barcodes" in single cells, we reconstructed early embryonic cell divisions. Targeted sequencing of clonal sSNVs in different organs (about 25,000×) and in more than 1000 cortical single cells, as well as single-nucleus RNA sequencing and single-nucleus assay for transposase-accessible chromatin sequencing of ~100,000 cortical single cells, demonstrated asymmetric contributions of early progenitors to extraembryonic tissues, distinct germ layers, and organs. Our data suggest onset of gastrulation at an effective progenitor pool of about 170 cells and about 50 to 100 founders for the forebrain. Thus, mosaic mutations provide a permanent record of human embryonic development at very high resolution.

MIPP-Seq: ultra-sensitive rapid detection and validation of low-frequency mosaic mutations.

BACKGROUND: Mosaic mutations contribute to numerous human disorders. As such, the identification and precise quantification of mosaic mutations is essential for a wide range of research applications, clinical diagnoses, and early detection of cancers. Currently, the low-throughput nature of single allele assays (e.g., allele-specific ddPCR) commonly used for genotyping known mutations at very low alternate allelic fractions (AAFs) have limited the integration of low-level mosaic analyses into clinical and research applications. The growing importance of mosaic mutations requires a more rapid, low-cost solution for mutation detection and validation. METHODS: To overcome these limitations, we developed Multiple Independent Primer PCR Sequencing (MIPP-Seq) which combines the power of ultra-deep sequencing and truly independent assays. The accuracy of MIPP-seq to quantifiable detect and measure extremely low allelic fractions was assessed using a combination of SNVs, insertions, and deletions at known allelic fractions in blood and brain derived DNA samples. RESULTS: The Independent amplicon analyses of MIPP-Seq markedly reduce the impact of allelic dropout, amplification bias, PCR-induced, and sequencing artifacts. Using low DNA inputs of either 25 ng or 50 ng of DNA, MIPP-Seq provides sensitive and quantitative assessments of AAFs as low as 0.025% for SNVs, insertion, and deletions. CONCLUSIONS: MIPP-Seq provides an ultra-sensitive, low-cost approach for detecting and validating known and novel mutations in a highly scalable system with broad utility spanning both research and clinical diagnostic testing applications. The scalability of MIPP-Seq allows for multiplexing mutations and samples, which dramatically reduce costs of variant validation when compared to methods like ddPCR. By leveraging the power of individual analyses of multiple unique and independent reactions, MIPP-Seq can validate and precisely quantitate extremely low AAFs across multiple tissues and mutational categories including both indels and SNVs. Furthermore, using Illumina sequencing technology, MIPP-seq provides a robust method for accurate detection of novel mutations at an extremely low AAF.

The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing.

We characterize the landscape of somatic mutations-mutations occurring after fertilization-in the human brain using ultra-deep (~250×) whole-genome sequencing of prefrontal cortex from 59 donors with autism spectrum disorder (ASD) and 15 control donors. We observe a mean of 26 somatic single-nucleotide variants per brain present in ≥4% of cells, with enrichment of mutations in coding and putative regulatory regions. Our analysis reveals that the first cell division after fertilization produces ~3.4 mutations, followed by 2-3 mutations in subsequent generations. This suggests that a typical individual possesses ~80 somatic single-nucleotide variants present in ≥2% of cells-comparable to the number of de novo germline mutations per generation-with about half of individuals having at least one potentially function-altering somatic mutation somewhere in the cortex. ASD brains show an excess of somatic mutations in neural enhancer sequences compared with controls, suggesting that mosaic enhancer mutations may contribute to ASD risk.

How Do Positive Psychological Constructs Affect Physical Activity Engagement Among Individuals at High Risk for Chronic Health Conditions? A Qualitative Study.

BACKGROUND: Positive psychological constructs (eg, optimism, positive affect) may help people engage in physical activity, though the details of these relationships and their directionality have not been studied in depth in people with cardiovascular risk factors. The objectives of this study were to use qualitative research to explore the relationships of positive psychological constructs with physical activity among people with metabolic syndrome. METHODS: Participants with metabolic syndrome and low physical activity from an academic medical center completed semistructured phone interviews about associations between physical activity and positive psychological constructs, and perceptions about benefits, motivation, and barriers to physical activity. RESULTS: The participants (n = 21) were predominantly older (mean age = 63 y) white (95.2%) women (61.9%). Engaging in physical activity was commonly associated with enjoyment, energy, relaxation, accomplishment, and determination. Experiencing positive psychological constructs like enjoyment, energy, connectedness, optimism, and determination also helped them engage in physical activity. Perceived benefits, facilitators, and barriers of physical activity engagement were noted. CONCLUSIONS: The participants at high risk for chronic diseases described many specific positive psychological constructs that both promote and result from physical activity. Testing ways to increase positive psychological constructs may be a novel way to help people at high risk of chronic diseases become more active.

Publisher Correction: Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A community-based positive psychology group intervention to promote physical activity among people with metabolic syndrome: Proof of concept results to inform a pilot randomized controlled trial protocol.

BACKGROUND: Community-based physical activity interventions can offset the burden of developing chronic diseases. Positive psychology (PP) interventions may improve health behaviors, but little is known about their effectiveness in community-based prevention settings. A multilevel PP-based intervention has never been studied in people at risk for chronic diseases. PURPOSE: The aim of the trial is to demonstrate feasibility, acceptability, and improve physical activity. The purpose is to describe the theory, design, and rationale of the randomized controlled trial (RCT) phase of an iteratively developed physical activity intervention for metabolic syndrome. The feasibility results of the proof-of-concept phase are presented. METHODS: Participants are adult primary care patients at community health centers with metabolic syndrome and low physical activity (target n = 64). The 8-week group intervention consists of weekly physical activity goal-setting and self-monitoring, positive psychology activities, and neighborhood walks. Participants rate feasibility and acceptability of sessions. Pre-post-intervention, and 24 weeks later, participants complete accelerometers, questionnaires, and biometrics. FEASIBILITY RESULTS: Eight participants enrolled and seven completed. The median number of group sessions attended was 7 out of 8. Average ease and usefulness of sessions were rated as 7.0 (±0.5)/10 and 8.1 (±1.0)/10, respectively, indicating feasibility and acceptability. Average pre-post physical activity increased by 2152 steps and 29.25 min of MVPA/week. DISCUSSION: This proof-of-concept trial demonstrated high feasibility and acceptability, with increased physical activity. These positive findings suggest that the RCT phase will show high feasibility, acceptability, and initial impact on physical activity.

Parallel RNA and DNA analysis after deep sequencing (PRDD-seq) reveals cell type-specific lineage patterns in human brain.

Elucidating the lineage relationships among different cell types is key to understanding human brain development. Here we developed parallel RNA and DNA analysis after deep sequencing (PRDD-seq), which combines RNA analysis of neuronal cell types with analysis of nested spontaneous DNA somatic mutations as cell lineage markers, identified from joint analysis of single-cell and bulk DNA sequencing by single-cell MosaicHunter (scMH). PRDD-seq enables simultaneous reconstruction of neuronal cell type, cell lineage, and sequential neuronal formation ("birthdate") in postmortem human cerebral cortex. Analysis of two human brains showed remarkable quantitative details that relate mutation mosaic frequency to clonal patterns, confirming an early divergence of precursors for excitatory and inhibitory neurons, and an "inside-out" layer formation of excitatory neurons as seen in other species. In addition our analysis allows an estimate of excitatory neuron-restricted precursors (about 10) that generate the excitatory neurons within a cortical column. Inhibitory neurons showed complex, subtype-specific patterns of neurogenesis, including some patterns of development conserved relative to mouse, but also some aspects of primate cortical interneuron development not seen in mouse. PRDD-seq can be broadly applied to characterize cell identity and lineage from diverse archival samples with single-cell resolution and in potentially any developmental or disease condition.

Weight bias internalization and its association with health behaviour adherence after bariatric surgery.

This study tested the hypothesis that internalized weight bias (WBI) is negatively associated with health-related quality of life, weight loss and health behaviour adherence (eg, physical activity, diet, vitamin adherence) in patients who had weight loss surgery (WLS). It also tested whether self-efficacy for exercise, barriers to being active and depression were mediators between WBI and moderate-to-vigorous physical activity (MVPA). Participants were recruited from online support forums. They completed an anonymous online survey assessing WBI, physical activity, health behaviour adherence, depression, health-related quality of life, self-efficacy for exercise and barriers to being physically active. Multiple regression analyses and a bootstrapping approach for mediation were used. The sample included 112 primarily white and female adults, who had surgery 1 month to 24 years prior. WBI was negatively associated with weight loss since surgery, MVPA, dietary adherence, vitamin adherence and mental health-related quality of life, and was not associated with walking, physical health-related quality of life or fluid intake adherence. Self-efficacy for exercise, barriers to being active and depression were partial mediators between WBI and physical activity. After WLS, WBI may signal poorer adherence to critical health behaviours. It also is associated with less weight loss. WBI should be assessed and treated by WLS providers.

The American Heart Association 2030 Impact Goal: A Presidential Advisory From the American Heart Association.

Each decade, the American Heart Association (AHA) develops an Impact Goal to guide its overall strategic direction and investments in its research, quality improvement, advocacy, and public health programs. Guided by the AHA's new Mission Statement, to be a relentless force for a world of longer, healthier lives, the 2030 Impact Goal is anchored in an understanding that to achieve cardiovascular health for all, the AHA must include a broader vision of health and well-being and emphasize health equity. In the next decade, by 2030, the AHA will strive to equitably increase healthy life expectancy beyond current projections, with global and local collaborators, from 66 years of age to at least 68 years of age across the United States and from 64 years of age to at least 67 years of age worldwide. The AHA commits to developing additional targets for equity and well-being to accompany this overarching Impact Goal. To attain the 2030 Impact Goal, we recommend a thoughtful evaluation of interventions available to the public, patients, providers, healthcare delivery systems, communities, policy makers, and legislators. This presidential advisory summarizes the task force's main considerations in determining the 2030 Impact Goal and the metrics to monitor progress. It describes the aspiration that these goals will be achieved by working with a diverse community of volunteers, patients, scientists, healthcare professionals, and partner organizations needed to ensure success.

Clinical-Community Partnerships to Identify Patients With Food Insecurity and Address Food Needs.

INTRODUCTION: More than 42 million people in the United States are food insecure. Although some health care entities are addressing food insecurity among patients because of associations with disease risk and management, little is known about the components of these initiatives. METHODS: The Systematic Screening and Assessment Method was used to conduct a landscape assessment of US health care entity-based programs that screen patients for food insecurity and connect them with food resources. A network of food insecurity researchers, experts, and practitioners identified 57 programs, 22 of which met the inclusion criteria of being health care entities that 1) screen patients for food insecurity, 2) link patients to food resources, and 3) target patients including adults aged 50 years or older (a focus of this assessment). Data on key features of each program were abstracted from documentation and telephone interviews. RESULTS: Most programs (n = 13) focus on patients with chronic disease, and most (n = 12) partner with food banks. Common interventions include referrals to or a list of food resources (n = 19), case managers who navigate patients to resources (n = 15), assistance with federal benefit applications (n = 14), patient education and skill building (n = 13), and distribution of fruit and vegetable vouchers redeemable at farmers markets (n = 8). Most programs (n = 14) routinely screen all patients. CONCLUSION: The programs reviewed use various strategies to screen patients, including older adults, for food insecurity and to connect them to food resources. Research is needed on program effectiveness in improving patient outcomes. Such evidence can be used to inform the investments of potential stakeholders, including health care entities, community organizations, and insurers.

Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.

We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.