3D genomic mapping reveals multifocality of human pancreatic precancers.

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study1. Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer.

Expressive vocabulary word categories of children who are deaf and hard-of-hearing.

This study investigated the acquisition of early expressive vocabulary among young children who are deaf and hard-of-hearing (DHH; n = 68) using auditory technology (hearing aids and cochlear implants). Parents completed a standardized vocabulary checklist, which allowed analyses of (i) the size of their child's spoken vocabulary; (ii) composition of the expressive lexicon (e.g., parts of speech such as nouns and verbs; semantic categories such as routines and body parts); and (iii) demographic and audiologic factors (e.g., chronologic age, degree of hearing access) potentially associated with these metrics. Young children who are DHH and use auditory technology acquired fewer spoken words than peers with typical hearing (TH) matched for chronologic age but more spoken words than peers with TH matched for listening experience. Action verbs-not nouns-significantly increased the odds of a child who is DHH achieving a vocabulary quotient within the normative range. These findings support the exploration of early expressive vocabulary size and composition-especially the number of active verbs-to guide clinical management and decision-making for young children who are DHH.

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

A Systems Approach for Assessing Low Back Pain Care Quality in Veterans Health Administration Chiropractic Visits: A Cross-Sectional Analysis.

OBJECTIVE: The purpose of this study was to explore a systemwide process for assessing components of low back pain (LBP) care quality in Veterans Health Administration (VHA) chiropractic visits using electronic health record (EHR) data. METHODS: We performed a cross-sectional quality improvement project. We randomly sampled 1000 on-station VHA chiropractic initial visits occurring from October 1, 2017, to September 30, 2018, for patients with no such visits within the prior 12 months. Characteristics of LBP visits were extracted from VHA national EHR data via structured data queries and manual chart review. We developed quality indicators for history and/or examination and treatment procedures using previously published literature and calculated frequencies of visits meeting these indicators. Visits meeting our history and/or examination and treatment indicators were classified as "high-quality" visits. We performed a regression analysis to assess associations between demographic/clinical characteristics and visits meeting our quality criteria. RESULTS: There were 592 LBP visits identified. Medical history, physical examination, and neurologic examination were documented in 76%, 77%, and 63% of all LBP visits, respectively. Recommended treatments, such as any manipulation, disease-specific education/advice, and therapeutic exercise, occurred in 75%, 69%, and 40% of chronic visits (n = 383), respectively. In acute/subacute visits (n = 37), any manipulation (92%), manual soft tissue therapy (57%), and disease-specific advice/education (54%) occurred most frequently. Female patients and those with a neck pain comorbid diagnosis were significantly less likely to have a "high-quality" visit, while other regression associations were non-significant. CONCLUSION: This study explored a systemwide process for assessing components of care quality in VHA chiropractic visits for LBP. These results produced a potential framework for uniform assessment of care quality in VHA chiropractic visits for LBP and highlight potential areas for improvements in LBP care quality assessments.

Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.

Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor ß signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.

Business vs After-Hours Use of an Artificial Intelligence-Powered Digital Health Platform Among Insured Patients.

This cross-sectional study assesses usage patterns of an AI-powered patient digital health platform.

Evaluating rates of chiropractic use and utilization by patient sex within the United States Veterans Health Administration: a serial cross-sectional analysis.

BACKGROUND: Within the United States Veterans Health Administration (VHA), the number of patients using healthcare services has increased over the past several decades. Females make up a small proportion of overall patients within the VHA; however, this proportion is growing rapidly. Previous studies have described rates of VHA chiropractic use; however, no prior study assessed differences in use or utilization rates between male and female veterans. The purpose of this study was to assess rates of use and utilization of chiropractic care by sex among VHA patients receiving care at VHA facilities with on-station chiropractic clinics. METHODS: A serial cross-sectional analysis of VHA national electronic health record data was conducted in Fall 2021 for fiscal year (FY) 2005-2021. The cohort population was defined as VHA facilities with on-station chiropractic clinics, and facilities were admitted to the cohort after the first FY with a minimum of 500 on-station chiropractic visits. Variables extracted included counts of unique users of any VHA on-station facility outpatient services, unique users of VHA on-station facility chiropractic services, number of chiropractic visits, and sex. To calculate use, we determined the proportion of patients of each sex who received chiropractic services to the total patients of the same sex receiving any outpatient care within each facility. To calculate utilization, we determined the number of chiropractic care visits per patient per fiscal year. A linear mixed effects model was applied to examine the difference in chiropractic care utilization by sex. RESULTS: The percentage of female VHA on-station chiropractic patients increased from 11.7 to 17.7% from FY2005-FY2021. Among VHA facilities with on-station chiropractic care, the percentage of female VHA healthcare users who used chiropractic care (mean = 2.3%) was greater than the percentage of male VHA healthcare users who used chiropractic care (mean = 1.1%). Rates of chiropractic utilization by sex among VHA facilities with on-station chiropractic clinics were slightly higher for females (median = 4.3 visits per year, mean = 4.9) compared to males (median = 4.1 visits per year, mean = 4.6). CONCLUSION: We report higher use and utilization of VHA chiropractic care by females compared with males, yet for both sexes rates were lower than in the private US healthcare system. This highlights the need for further assessment of the determinants and outcomes of VHA chiropractic care.

Weight loss and modeled cost savings in a digital diabetes prevention program.

Background: Participation in the National Diabetes Prevention Program (DPP) can improve individual health through reduced risk of type 2 diabetes and save the healthcare system substantial medical costs associated with a diagnosis of type 2 diabetes and its associated complications. There is less evidence of outcomes and cost savings associated with a fully digital delivery of the DPP. Methods: This study assessed 13,593 members who provided an initial digital weight and subsequently achieved various weight loss and engagement outcomes during their participation in a digital DPP. Analyzed data included both complete observations and missing observations imputed using maximum likelihood estimation. Findings include members' behavioral correlates of weight loss and a literature-based cost-savings estimate associated with achieving three mutually exclusive weight loss or engagement benchmarks: ≥5% weight loss, >2% but <5% weight loss, and completion of ≥4 educational lessons. Results: 11,976 members (88%) provided a weight after 2 months of participation, enabling calculation of their weight nadir. Considering complete data, 97% of members maintained or lost weight. Using the imputed data for these calculations, 32.0% of members achieved ≥5%, 32.4% achieved >2% but <5%, 32.0% maintained ±2%, and 3.6% gained weight. Members who lost the most weight achieved their weight nadir furthest into the program (mean day = 189, SE = 1.4) and had the longest active engagement (mean days = 268, SE = 1.4), particularly compared to members who gained weight (mean nadir day = 119, SE = 3.7; active engagement mean days = 199, SE = 4.9) (both p ≤ 0.0001). Modeled 1-year cost-savings estimates ranged from $11,229,160 to $12,960,875. Conclusions: Members of a fully digital DPP achieved clinical and engagement outcomes during their participation in the program that confer important health benefits and cost savings.

Predictors of program interest in a digital health pilot study for heart health.

Digital health programs can play a key role in supporting lifestyle changes to prevent and reduce cardiovascular disease (CVD) risk. A key concern for new programs is understanding who is interested in participating. Thus, the primary objective of this study was to utilize electronic health records (EHR) to predict interest in a digital health app called Lark Heart Health. Because prior studies indicate that males are less likely to utilize prevention-focused digital health programs, secondary analyses assessed sex differences in recruitment and enrollment. Data were drawn from an ongoing pilot study of the Heart Health program, which provides digital health behavior coaching and surveys for CVD prevention. EHR data were used to predict whether potential program participants who received a study recruitment email showed interest in the program by "clicking through" on the email to learn more. Primary objective analyses used backward elimination regression and eXtreme Gradient Boost modeling. Recruitment emails were sent to 8,649 patients with available EHR data; 1,092 showed interest (i.e., clicked through) and 345 chose to participate in the study. EHR variables that predicted higher odds of showing interest were higher body mass index (BMI), fewer elevated lab values, lower HbA1c, non-smoking status, and identifying as White. Secondary objective analyses showed that, males and females showed similar program interest and were equally represented throughout recruitment and enrollment. In summary, BMI, elevated lab values, HbA1c, smoking status, and race emerged as key predictors of program interest; conversely, sex, age, CVD history, history of chronic health issues, and medication use did not predict program interest. We also found no sex differences in the recruitment and enrollment process for this program. These insights can aid in refining digital health tools to best serve those interested, as well as highlight groups who may benefit from behavioral intervention tools promoted by additional recruitment efforts tailored to their interest.

Quasi-experimental, Nonrandomized Initiative to Minimize Sleep Disruptions among Hospitalized Children.

Hospitalized children experience frequent sleep disruptions. We aimed to reduce caregiver-reported sleep disruptions of children hospitalized on the pediatric hospital medicine service by 10% over 12 months. Methods: In family surveys, caregivers cited overnight vital signs (VS) as a primary contributor to sleep disruption. We created a new VS frequency order of "every 4 hours (unless asleep between 2300 and 0500)" as well as a patient list column in the electronic health record indicating patients with this active VS order. The outcome measure was caregiver-reported sleep disruptions. The process measure was adherence to the new VS frequency. The balancing measure was rapid responses called on patients with the new VS frequency. Results: Physician teams ordered the new VS frequency for 11% (1,633/14,772) of patient nights on the pediatric hospital medicine service. Recorded VS between 2300 and 0500 was 89% (1,447/1,633) of patient nights with the new frequency ordered compared to 91% (11,895/13,139) of patient nights without the new frequency ordered (P = 0.01). By contrast, recorded blood pressure between 2300 and 0500 was only 36% (588/1,633) of patient nights with the new frequency but 87% (11,478/13,139) of patient nights without the new frequency (P < 0.001). Overall, caregivers reported sleep disruptions on 24% (99/419) of reported nights preintervention, which decreased to 8% (195/2,313) postintervention (P < 0.001). Importantly, there were no adverse safety issues related to this initiative. Conclusion: This study safely implemented a new VS frequency with reduced overnight blood pressure readings and caregiver-reported sleep disruptions.

Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program.

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size.

Curating a body-positive feed? An attempt to mitigate the negative impacts of thin-ideal content on Instagram.

Over the last decade, research has shown a negative relationship between social media use and body image. For women, these adverse effects tend to result from viewing content that promotes thinness as the ideal body type. Attempts to mitigate these adverse effects using disclaimers have failed. In the current study, we tested whether interspersing thin-ideal content with body-positive posts can mitigate the impact of thin-ideal content. The current study had six conditions. In three conditions, participants were exposed to 20 images of either thin-ideal, body-positive, or nature (control) images from Instagram. In the remaining three conditions, we interspersed the 20 images from the thin-deal condition with either 1 (i.e., 1:20 condition), 2 (i.e., 1:10 condition), or 4 (i.e., 1:5 condition) body-positive posts. For all six conditions, body satisfaction, body appreciation, appearance self-esteem, positive affect, and negative affect were measured before and after exposure. Our results demonstrated that irrespective of frequency, interspersing thin-ideal content with body-positive content did not mitigate decreases in body satisfaction, body appreciation, appearance self-esteem, or positive affect. Our failure to mitigate the negative impact of thin-ideal content adds to a growing body of work demonstrating that combating the impact of thin-ideal content on Instagram is extremely difficult.

Weight Loss in a Digital Diabetes Prevention Program for People in Health Professional Shortage and Rural Areas.

Individuals with prediabetes living in hard-to-reach and underserved areas experience barriers to accessing traditional in-person preventive health services. The National Diabetes Prevention Program (DPP) is a preventive health care program designed to reduce the risk of developing type 2 diabetes. Although there have been increasing numbers of remote DPPs accessible, there are little data on the clinical outcomes of digital DPPs for members living in hard-to-reach and underserved areas. This study assessed whether living in a designated Health Professional Shortage Area (HPSA) and a rural versus urban area impacted the weight loss of N = 7266 members of a fully digital program called Lark DPP. Secondary analyses included between-group comparisons of program retention and member characteristics, demographics, and socioeconomics. Percent weight loss did not differ by HPSA (P = 0.16) or rural/urban status (P = 0.15), despite greater potential barriers for members residing in HPSAs (eg, highest starting body mass index, lowest income, lowest education). Mean percent weight loss for members residing in an HPSA and rural area was mean (M) = 4.75%, standard error (SE) = 0.09; for members in a non-HPSA, rural area M = 4.96%, SE = 0.16; for members in an HPSA, urban area M = 4.55%, SE = 0.13; and for members in a non-HPSA, urban area M = 4.77%, SE = 0.13. Members of a fully digital DPP achieved weight loss that did not differ by HPSA or urban/rural designation. Fully digital programs offer a solution to reduce the risk of type 2 diabetes in areas where residents may not otherwise have access to diabetes prevention services.

Three-dimensional genomic mapping of human pancreatic tissue reveals striking multifocality and genetic heterogeneity in precancerous lesions.

Pancreatic intraepithelial neoplasia (PanIN) is a precursor to pancreatic cancer and represents a critical opportunity for cancer interception. However, the number, size, shape, and connectivity of PanINs in human pancreatic tissue samples are largely unknown. In this study, we quantitatively assessed human PanINs using CODA, a novel machine-learning pipeline for 3D image analysis that generates quantifiable models of large pieces of human pancreas with single-cell resolution. Using a cohort of 38 large slabs of grossly normal human pancreas from surgical resection specimens, we identified striking multifocality of PanINs, with a mean burden of 13 spatially separate PanINs per cm3 of sampled tissue. Extrapolating this burden to the entire pancreas suggested a median of approximately 1000 PanINs in an entire pancreas. In order to better understand the clonal relationships within and between PanINs, we developed a pipeline for CODA-guided multi-region genomic analysis of PanINs, including targeted and whole exome sequencing. Multi-region assessment of 37 PanINs from eight additional human pancreatic tissue slabs revealed that almost all PanINs contained hotspot mutations in the oncogene KRAS, but no gene other than KRAS was altered in more than 20% of the analyzed PanINs. PanINs contained a mean of 13 somatic mutations per region when analyzed by whole exome sequencing. The majority of analyzed PanINs originated from independent clonal events, with distinct somatic mutation profiles between PanINs in the same tissue slab. A subset of the analyzed PanINs contained multiple KRAS mutations, suggesting a polyclonal origin even in PanINs that are contiguous by rigorous 3D assessment. This study leverages a novel 3D genomic mapping approach to describe, for the first time, the spatial and genetic multifocality of human PanINs, providing important insights into the initiation and progression of pancreatic neoplasia.

A fast linkage method for population GWAS cohorts with related individuals.

Linkage analysis, a class of methods for detecting co-segregation of genomic segments and traits in families, was used to map disease-causing genes for decades before genotyping arrays and dense SNP genotyping enabled genome-wide association studies in population samples. Population samples often contain related individuals, but the segregation of alleles within families is rarely used because traditional linkage methods are computationally inefficient for larger datasets. Here, we describe Population Linkage, a novel application of Haseman-Elston regression as a method of moments estimator of variance components and their standard errors. We achieve additional computational efficiency by using modern methods for detection of IBD segments and variance component estimation, efficient preprocessing of input data, and minimizing redundant numerical calculations. We also refined variance component models to account for the biases in population-scale methods for IBD segment detection. We ran Population Linkage on four blood lipid traits in over 70,000 individuals from the HUNT and SardiNIA studies, successfully detecting 25 known genetic signals. One notable linkage signal that appeared in both was for low-density lipoprotein (LDL) cholesterol levels in the region near the gene APOE (LOD = 29.3, variance explained = 4.1%). This is the region where the missense variants rs7412 and rs429358, which together make up the ε2, ε3, and ε4 alleles each account for 2.4% and 0.8% of variation in circulating LDL cholesterol. Our results show the potential for linkage analysis and other large-scale applications of method of moments variance components estimation.

A Reduced Pancreatic Polypeptide Response is Associated With New-onset Pancreatogenic Diabetes Versus Type 2 Diabetes.

PURPOSE: Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM). METHODS: Subjects with new-onset DM (<3 years' duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of PP concentrations between groups were performed using Wilcoxon rank-sum test and analysis of covariance while adjusting for age, sex, and body mass index. RESULTS: The fasting PP concentration was lower in both the PDAC-DM and CP-DM groups than in the T2DM group (P = 0.03 and <0.01, respectively). The fold change in PP at 15 minutes following meal stimulation was significantly lower in the PDAC-DM (median, 1.869) and CP-DM (1.813) groups compared with T2DM (3.283; P < 0.01 for both comparisons). The area under the curve of PP concentration was significantly lower in both the PDAC-DM and CP-DM groups than in T2DM regardless of the interval used for calculation and remained significant after adjustments. CONCLUSIONS: Fasting PP concentrations and the response to meal stimulation are reduced in new-onset DM associated with PDAC or CP compared with T2DM. These findings support further investigations into the use of PP concentrations to characterize pancreatogenic DM and to understand the pathophysiological role in exocrine pancreatic diseases (NCT03460769).

Intraparenchymal metastases as a cause for local recurrence of pancreatic cancer.

Using CODA, a technique for three-dimensional reconstruction of large tissues, Kiemen et al. report observation of a microscopic focus of pancreatic cancer found in the vasculature of grossly normal human pancreas tissue resected adjacent to a large tumour. They use TP53 and SMAD4 staining to relate the small focus to the primary tumour. This report describes a represents a probable case of intraparenchymal metastasis of pancreatic cancer, revealing a probable cause of local recurrence.