Precision Phenotyping for Curating Research Cohorts of Patients with Post-Acute Sequelae of COVID-19 (PASC) as a Diagnosis of Exclusion.

Scalable identification of patients with the post-acute sequelae of COVID-19 (PASC) is challenging due to a lack of reproducible precision phenotyping algorithms and the suboptimal accuracy, demographic biases, and underestimation of the PASC diagnosis code (ICD-10 U09.9). In a retrospective case-control study, we developed a precision phenotyping algorithm for identifying research cohorts of PASC patients, defined as a diagnosis of exclusion. We used longitudinal electronic health records (EHR) data from over 295 thousand patients from 14 hospitals and 20 community health centers in Massachusetts. The algorithm employs an attention mechanism to exclude sequelae that prior conditions can explain. We performed independent chart reviews to tune and validate our precision phenotyping algorithm. Our PASC phenotyping algorithm improves precision and prevalence estimation and reduces bias in identifying Long COVID patients compared to the U09.9 diagnosis code. Our algorithm identified a PASC research cohort of over 24 thousand patients (compared to about 6 thousand when using the U09.9 diagnosis code), with a 79.9 percent precision (compared to 77.8 percent from the U09.9 diagnosis code). Our estimated prevalence of PASC was 22.8 percent, which is close to the national estimates for the region. We also provide an in-depth analysis outlining the clinical attributes, encompassing identified lingering effects by organ, comorbidity profiles, and temporal differences in the risk of PASC. The PASC phenotyping method presented in this study boasts superior precision, accurately gauges the prevalence of PASC without underestimating it, and exhibits less bias in pinpointing Long COVID patients. The PASC cohort derived from our algorithm will serve as a springboard for delving into Long COVID's genetic, metabolomic, and clinical intricacies, surmounting the constraints of recent PASC cohort studies, which were hampered by their limited size and available outcome data.

Epigenome-wide association study of lung cancer among never smokers in two prospective cohorts in Shanghai, China.

BACKGROUND: The aetiology of lung cancer among individuals who never smoked remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Epigenetic alterations, particularly DNA methylation (DNAm) changes, have emerged as potential drivers. Yet, few prospective epigenome-wide association studies (EWAS), primarily focusing on peripheral blood DNAm with limited representation of never smokers, have been conducted. METHODS: We conducted a nested case-control study of 80 never-smoking incident lung cancer cases and 83 never-smoking controls within the Shanghai Women's Health Study and Shanghai Men's Health Study. DNAm was measured in prediagnostic oral rinse samples using Illumina MethylationEPIC array. Initially, we conducted an EWAS to identify differentially methylated positions (DMPs) associated with lung cancer in the discovery sample of 101 subjects. The top 50 DMPs were further evaluated in a replication sample of 62 subjects, and results were pooled using fixed-effect meta-analysis. RESULTS: Our study identified three DMPs significantly associated with lung cancer at the epigenome-wide significance level of p<8.22×10-8. These DMPs were identified as cg09198866 (MYH9; TXN2), cg01411366 (SLC9A10) and cg12787323. Furthermore, examination of the top 1000 DMPs indicated significant enrichment in epithelial regulatory regions and their involvement in small GTPase-mediated signal transduction pathways. Additionally, GrimAge acceleration was identified as a risk factor for lung cancer (OR=1.19 per year; 95% CI 1.06 to 1.34). CONCLUSIONS: While replication in a larger sample size is necessary, our findings suggest that DNAm patterns in prediagnostic oral rinse samples could provide novel insights into the underlying mechanisms of lung cancer in never smokers.

A prospective study of smoking-related white blood cell DNA methylation markers and risk of bladder cancer.

Bladder cancer, a common neoplasm, is primarily caused by tobacco smoking. Epigenetic alterations including DNA methylation have the potential to be used as prospective markers of increased risk, particularly in at-risk populations such as smokers. We aimed to investigate the potential of smoking-related white blood cell (WBC) methylation markers to contribute to an increase in bladder cancer risk prediction over classical questionnaire-based smoking metrics (i.e., duration, intensity, packyears) in a nested case-control study within the prospective prostate, lung, colorectal, and ovarian (PLCO) Cancer Screening Trial and the alpha-tocopherol, beta-carotene cancer (ATBC) Prevention Study (789 cases; 849 controls). We identified 200 differentially methylated sites associated with smoking status and 28 significantly associated (after correction for multiple testing) with bladder cancer risk among 2670 previously reported smoking-related cytosine-phosphate-guanines sites (CpGs). Similar patterns were observed across cohorts. Receiver operating characteristic (ROC) analyses indicated that cg05575921 (AHHR), the strongest smoking-related association we identified for bladder cancer risk, alone yielded similar predictive performance (AUC: 0.60) than classical smoking metrics (AUC: 0.59-0.62). Best prediction was achieved by including the first principal component (PC1) from the 200 smoking-related CpGs alongside smoking metrics (AUC: 0.63-0.65). Further, PC1 remained significantly associated with elevated bladder cancer risk after adjusting for smoking metrics. These findings suggest DNA methylation profiles reflect aspects of tobacco smoke exposure in addition to those captured by smoking duration, intensity and packyears, and/or individual susceptibility relevant to bladder cancer etiology, warranting further investigation.

Structure and Funding of Clinical Informatics Fellowships: A National Survey of Program Directors.

BACKGROUND: In 2011, the American Board of Medical Specialties established clinical informatics (CI) as a subspecialty in medicine, jointly administered by the American Board of Pathology and the American Board of Preventive Medicine. Subsequently, many institutions created CI fellowship training programs to meet the growing need for informaticists. Although many programs share similar features, there is considerable variation in program funding and administrative structures. OBJECTIVES: The aim of our study was to characterize CI fellowship program features, including governance structures, funding sources, and expenses. METHODS: We created a cross-sectional online REDCap survey with 44 items requesting information on program administration, fellows, administrative support, funding sources, and expenses. We surveyed program directors of programs accredited by the Accreditation Council for Graduate Medical Education between 2014 and 2021. RESULTS: We invited 54 program directors, of which 41 (76%) completed the survey. The average administrative support received was $27,732/year. Most programs (85.4%) were accredited to have two or more fellows per year. Programs were administratively housed under six departments: Internal Medicine (17; 41.5%), Pediatrics (7; 17.1%), Pathology (6; 14.6%), Family Medicine (6; 14.6%), Emergency Medicine (4; 9.8%), and Anesthesiology (1; 2.4%). Funding sources for CI fellowship program directors included: hospital or health systems (28.3%), clinical departments (28.3%), graduate medical education office (13.2%), biomedical informatics department (9.4%), hospital information technology (9.4%), research and grants (7.5%), and other sources (3.8%) that included philanthropy and external entities. CONCLUSION: CI fellowships have been established in leading academic and community health care systems across the country. Due to their unique training requirements, these programs require significant resources for education, administration, and recruitment. There continues to be considerable heterogeneity in funding models between programs. Our survey findings reinforce the need for reformed federal funding models for informatics practice and training.

Pharmacist-Led Diabetes Control Intervention and Health Outcomes in Hispanic Patients With Diabetes.

Importance: Among patients with type 2 diabetes (T2D), Hispanic individuals are more likely than non-Hispanic White individuals to develop diabetes-related complications. Objective: To examine the association of a pharmacist-led intervention (UCMyRx) with hemoglobin A1c (HbA1c) and systolic blood pressure (SBP) among Hispanic patients with T2D. Design, Setting, and Participants: This quality improvement study used electronic health record data and a difference-in-differences study design to evaluate the association of UCMyRx exposure with changes in HbA1c concentration and SBP among Hispanic patients with T2D, relative to usual care, at University of California, Los Angeles primary care clinics between February and April of 2023. The study population included patients with an International Classification of Diseases, Ninth Revision/International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis of T2D, self-reporting Hispanic ethnicity, age 18 years or older, with 1 or more visits with a UCMyRx pharmacist (treatment) or 2 or more visits, 2 or more years apart, during the study window (comparison). Additionally, patients had to have the following observations during the study window (March 2, 2013-December 31, 2018): (1) a HbA1c 8% or higher, anywhere between 365 days before and 14 days after the index date (date of the first UCMyRx visit or a randomly generated index date) and a follow-up HbA1c measure within 120 to 365 days after the index date (n = 396) and/or (2) a SBP 140 mm Hg or higher between 365 days before and 14 days after the index date, and a follow-up SBP measure within 120 to 450 days after the index date (n = 795). Exposure: Pharmacists review laboratory results/vital signs, perform medication reconciliation, and develop personally tailored interventions to address adherence barriers and increase guideline-concordant care. Main Outcomes and Measures: Pre- to post-index date changes in HbA1c and SBP. Results: Of the 931 unique patients with T2D analyzed, the mean (SD) age was 64 (14.1) years, and 552 (59.3%) were female. In adjusted analyses, having 1 or more UCMyRx visits was associated with a reduction in HbA1c concentration (ß = -0.46%; 95% CI, -0.84% to -0.07%) but no change in SBP (ß = -1.71 mm Hg; 95% CI, -4.00 to 0.58 mm Hg). Conclusions and Relevance: In this quality improvement study of UCMyRx among Hispanic patients with T2D, a negative association was observed between UCMyRx exposure and HbA1c concentration but not SBP. Pharmacist-led intervention may be a strategy for improving outcomes among Hispanic patients with T2D.

Evaluating the predictive ability of natural language processing in identifying tertiary/quaternary cases in prioritization workflows for interhospital transfer.

Objectives: Tertiary and quaternary (TQ) care refers to complex cases requiring highly specialized health services. Our study aimed to compare the ability of a natural language processing (NLP) model to an existing human workflow in predictively identifying TQ cases for transfer requests to an academic health center. Materials and methods: Data on interhospital transfers were queried from the electronic health record for the 6-month period from July 1, 2020 to December 31, 2020. The NLP model was allowed to generate predictions on the same cases as the human predictive workflow during the study period. These predictions were then retrospectively compared to the true TQ outcomes. Results: There were 1895 transfer cases labeled by both the human predictive workflow and the NLP model, all of which had retrospective confirmation of the true TQ label. The NLP model receiver operating characteristic curve had an area under the curve of 0.91. Using a model probability threshold of ≥0.3 to be considered TQ positive, accuracy was 81.5% for the NLP model versus 80.3% for the human predictions (P = .198) while sensitivity was 83.6% versus 67.7% (P<.001). Discussion: The NLP model was as accurate as the human workflow but significantly more sensitive. This translated to 15.9% more TQ cases identified by the NLP model. Conclusion: Integrating an NLP model into existing workflows as automated decision support could translate to more TQ cases identified at the onset of the transfer process.

Embedding research study recruitment within the patient portal preCheck-in.

OBJECTIVE: Patient portals are increasingly used to recruit patients in research studies, but communication response rates remain low without tactics such as financial incentives or manual outreach. We evaluated a new method of study enrollment by embedding a study information sheet and HIPAA authorization form (HAF) into the patient portal preCheck-in (where patients report basic information like allergies). MATERIALS AND METHODS: Eligible patients who enrolled received an after-visit patient-reported outcomes survey through the patient portal. No additional recruitment/messaging efforts were made. RESULTS: A total of 386 of 843 patients completed preCheck-in, 308 of whom signed the HAF and enrolled in the study (37% enrollment rate). Of 93 patients who were eligible to receive the after-visit survey, 45 completed it (48% completion rate). CONCLUSION: Enrollment and survey completion rates were higher than what is typically seen with recruitment by patient portal messaging, suggesting that preCheck-in recruitment can enhance research study recruitment and warrants further investigation.

Whole-genome survey reveals extensive variation in genetic diversity and inbreeding levels among peregrine falcon subspecies.

In efforts to prevent extinction, resource managers are often tasked with increasing genetic diversity in a population of concern to prevent inbreeding depression or improve adaptive potential in a changing environment. The assumption that all small populations require measures to increase their genetic diversity may be unwarranted, and limited resources for conservation may be better utilized elsewhere. We test this assumption in a case study focused on the peregrine falcon (Falco peregrinus), a cosmopolitan circumpolar species with 19 named subspecies. We used whole-genome resequencing to generate over two million single nucleotide polymorphisms (SNPs) from multiple individuals of all peregrine falcon subspecies. Our analyses revealed extensive variation among subspecies, with many island-restricted and nonmigratory populations possessing lower overall genomic diversity, elevated inbreeding coefficients (F ROH)-among the highest reported, and extensive runs of homozygosity (ROH) compared to mainland and migratory populations. Similarly, the majority of subspecies that are either nonmigratory or restricted to islands show a much longer history of low effective population size (N e). While mutational load analyses indicated an increased proportion of homozygous-derived deleterious variants (i.e., drift load) among nonmigrant and island populations compared to those that are migrant or reside on the mainland, no significant differences in the proportion of heterozygous deleterious variants (i.e., inbreeding load) was observed. Our results provide evidence that high levels of inbreeding may not be an existential threat for some populations or taxa. Additional factors such as the timing and severity of population declines are important to consider in management decisions about extinction potential.

Prospective epigenome and transcriptome analyses of cord and peripheral blood from preterm infants at risk of bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease of prematurity with limited treatment options. To uncover biomarkers of BPD risk, this study investigated epigenetic and transcriptomic signatures of prematurity at birth and during the neonatal period at day 14 and 28. Peripheral blood DNAs from preterm infants were applied to methylation arrays and cell-type composition was estimated by deconvolution. Covariate-adjusted robust linear regression elucidated BPD- and prolonged oxygen (≥ 14 days) exposure-associated CpGs. RNAs from cord and peripheral blood were sequenced, and differentially expressed genes (DEGs) for BPD or oxygen exposure were determined. Estimated neutrophil-lymphocyte ratios in peripheral blood at day 14 in BPD infants were significantly higher than nonBPD infants, suggesting an heightened inflammatory response in developing BPD. BPD-DEGs in cord blood indicated lymphopoiesis inhibition, altered Th1/Th2 responses, DNA damage, and organ degeneration. On day 14, BPD-associated CpGs were highly enriched in neutrophil activation, infection, and CD4 + T cell quantity, and BPD-DEGs were involved in DNA damage, cellular senescence, T cell homeostasis, and hyper-cytokinesis. On day 28, BPD-associated CpGs along with BPD-DEGs were enriched for phagocytosis, neurological disorder, and nucleotide metabolism. Oxygen supplementation markedly downregulated mitochondrial biogenesis genes and altered CpGs annotated to developmental genes. Prematurity-altered DNA methylation could cause abnormal lymphopoiesis, cellular assembly and cell cycle progression to increase BPD risk. Similar pathways between epigenome and transcriptome networks suggest coordination of the two in dysregulating leukopoiesis, adaptive immunity, and innate immunity. The results provide molecular insights into biomarkers for early detection and prevention of BPD.

A Multicenter Retrospective Cohort Study to Characterize Patients Hospitalized With Multisystem Inflammatory Syndrome in Adults and Coronavirus Disease 2019 in the United States, 2020-2021.

BACKGROUND: The diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated multisystem inflammatory syndrome in adults (MIS-A) requires distinguishing it from acute coronavirus disease 2019 (COVID-19) and may affect clinical management. METHODS: In this retrospective cohort study, we applied the US Centers for Disease Control and Prevention case definition to identify adults hospitalized with MIS-A at 6 academic medical centers from 1 March 2020 to 31 December 2021. Patients MIS-A were matched by age group, sex, site, and admission date at a 1:2 ratio to patients hospitalized with acute symptomatic COVID-19. Conditional logistic regression was used to compare demographic characteristics, presenting symptoms, laboratory and imaging results, treatments administered, and outcomes between cohorts. RESULTS: Through medical record review of 10 223 patients hospitalized with SARS-CoV-2-associated illness, we identified 53 MIS-A cases. Compared with 106 matched patients with COVID-19, those with MIS-A were more likely to be non-Hispanic black and less likely to be non-Hispanic white. They more likely had laboratory-confirmed COVID-19 ≥14 days before hospitalization, more likely had positive in-hospital SARS-CoV-2 serologic testing, and more often presented with gastrointestinal symptoms and chest pain. They were less likely to have underlying medical conditions and to present with cough and dyspnea. On admission, patients with MIS-A had higher neutrophil-to-lymphocyte ratio and higher levels of C-reactive protein, ferritin, procalcitonin, and D-dimer than patients with COVID-19. They also had longer hospitalization and more likely required intensive care admission, invasive mechanical ventilation, and vasopressors. The mortality rate was 6% in both cohorts. CONCLUSIONS: Compared with patients with acute symptomatic COVID-19, adults with MIS-A more often manifest certain symptoms and laboratory findings early during hospitalization. These features may facilitate diagnosis and management.

Epigenomic profiling of isolated blood cell types reveals highly specific B cell smoking signatures and links to disease risk.

BACKGROUND: Tobacco smoking alters the DNA methylation profiles of immune cells which may underpin some of the pathogenesis of smoking-associated diseases. To link smoking-driven epigenetic effects in specific immune cell types with disease risk, we isolated six leukocyte subtypes, CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, CD4+ T cells, CD8+ T cells, and CD56+ natural killer cells, from whole blood of 67 healthy adult smokers and 74 nonsmokers for epigenome-wide association study (EWAS) using Illumina 450k and EPIC methylation arrays. RESULTS: Numbers of smoking-associated differentially methylated sites (smCpGs) at genome-wide significance (p < 1.2 × 10-7) varied widely across cell types, from 5 smCpGs in CD8+ T cells to 111 smCpGs in CD19+ B cells. We found unique smoking effects in each cell type, some of which were not apparent in whole blood. Methylation-based deconvolution to estimate B cell subtypes revealed that smokers had 7.2% (p = 0.033) less naïve B cells. Adjusting for naïve and memory B cell proportions in EWAS and RNA-seq allowed the identification of genes enriched for B cell activation-related cytokine signaling pathways, Th1/Th2 responses, and hematopoietic cancers. Integrating with large-scale public datasets, 62 smCpGs were among CpGs associated with health-relevant EWASs. Furthermore, 74 smCpGs had reproducible methylation quantitative trait loci single nucleotide polymorphisms (SNPs) that were in complete linkage disequilibrium with genome-wide association study SNPs, associating with lung function, disease risks, and other traits. CONCLUSIONS: We observed blood cell-type-specific smCpGs, a naïve-to-memory shift among B cells, and by integrating genome-wide datasets, we identified their potential links to disease risks and health traits.

The Application of Dental Fluoride Varnish in Children: A Low Cost, High-Value Implementation Aided by Passive Clinical Decision Support.

BACKGROUND: Fluoride is vital in the prevention of dental caries in children. In 2014, the U.S. Preventive Services Task Force deemed fluoride varnish a recommended preventive service (grade B). Electronic health record-based clinical decision support (CDS) tools have shown variable ability to alter physicians' ordering behaviors. OBJECTIVES: This study aimed to increase the application of fluoride varnish in children while analyzing the effect of two passive CDS tools-an order set and a note template. METHODS: Data on outpatient pediatric visits over an 18-month period before and after CDS implementation (October 15, 2020-April 15, 2022) were queried, while trends in application rate of fluoride were examined. We constructed a multiple logistic regression model with a primary outcome of whether a patient received fluoride at his/her visit. The primary predictor was a "phase" variable representing the CDS implemented. Physician interaction with CDS as well as the financial effects of the resulting service use were also examined. RESULTS: There were 3,049 well-child visits of children aged 12 months to 5 years. The addition of a fluoride order to a "Well Child Check" order set led to a 10.6% increase in ordering over physician education alone (25.4 vs. 14.8%, p = 0.001), while the insertion of fluoride-specific text to drop-down lists in clinical notes led to a 6.2% increase (31.5 vs. 25.4%, p = 0.005). Whether a patient received topical fluoride was positively associated with order set implementation (odds ratio [OR] = 5.87, 95% confidence interval [CI]: 4.20-8.21) and fluoride-specific drop-down lists (OR = 7.81, 95% CI: 5.41-11.28). Female providers were more likely to use order sets when ordering fluoride (56.2 vs. 40.9% for males, p ≤ 0.0001). Added revenue totaled $15,084. CONCLUSION: The targeted use of order sets and note templates was positively associated with the ordering of topical fluoride by physicians.

Feeding Neonates and Infants Prior to Surgery for Congenital Heart Defects: Systematic Review and Meta-Analysis.

BACKGROUND: Necrotising enterocolitis (NEC) is a significant cause of mortality and morbidity in neonates requiring cardiac surgery. Feeding practices vary significantly across institutions and remain controversial. We conducted a systematic review of the literature and a meta-analysis to identify associations between feeding practices and necrotising enterocolitis. METHODS: This study was carried out in accordance with the PRISMA guidelines. A literature search was performed in November 2022 using the Cochrane Central Register, Embase, and Pubmed. Two investigators then independently retrieved eligible manuscripts considered suitable for inclusion. Data extracted included gestational age, birth weight, sex, nature of congenital heart lesion, type of operation performed, time on ventilator, ICU stay, hospital stay, post-operative feeding strategy, and complications. The methodological quality was assessed using the Downs and Black score for all randomised control trials and observational studies. RESULTS: The initial search yielded 92 studies. After removing duplicates, there were 85 abstracts remaining. After excluding ineligible studies, 8 studies were included for the meta-analysis. There was no significant risk of NEC associated with pre-operative feeding [OR = 1.22 (95% CI 0.77,1.92)] or umbilical artery catheter placement [OR = 0.91 (95% CI 0.44, 1.89)] and neither outcome exhibited heterogeneity [I2 = 8% and 0%, respectively]. There was a significant association between HLHS and NEC [OR = 2.56 (95% CI 1.56, 4.19)] as well as prematurity and NEC [OR 3.34 (95% CI 1.94, 5.75)] and neither outcome exhibited heterogeneity [I2 = 0% and 0%, respectively]. CONCLUSIONS: There was no association between NEC and pre-operative feeding status in neonates awaiting cardiac surgery. Pre-operative feeding status was not associated with prolonged hospital stay or need for tube assisted feeding at discharge. HLHS and prematurity were associated with increased incidence of NEC.

Distinct components of alert fatigue in physicians' responses to a noninterruptive clinical decision support alert.

OBJECTIVE: Clinical decision support (CDS) alerts may improve health care quality but "alert fatigue" can reduce provider responsiveness. We analyzed how the introduction of competing alerts affected provider adherence to a single depression screening alert. MATERIALS AND METHODS: We analyzed the audit data from all occurrences of a CDS alert at a large academic health system. For patients who screen positive for depression during ambulatory visits, a noninterruptive alert was presented, offering a number of relevant documentation actions. Alert adherence was defined as the selection of any option offered within the alert. We assessed the effect of competing clinical guidance alerts presented during the same encounter and the total of all CDS alerts that the same provider had seen in the prior 90 days, on the probability of depression screen alert adherence, adjusting for physician and patient characteristics. RESULTS: The depression alert fired during 55 649 office visits involving 418 physicians and 40 474 patients over 41 months. After adjustment, physicians who had seen the most alerts in the prior 90 days were much less likely to respond (adjusted OR highest-lowest quartile, 0.38; 95% CI 0.35-0.42; P < .001). Competing alerts in the same visit further reduced the likelihood of adherence only among physicians in the middle two quartiles of alert exposure in the prior 90 days. CONCLUSIONS: Adherence to a noninterruptive depression alert was strongly associated with the provider's cumulative alert exposure over the past quarter. Health systems should monitor providers' recent alert exposure as a measure of alert fatigue.

An Effectiveness Study of a Primary Care-embedded Clinical Pharmacist-Led Intervention Among Patients With Diabetes and Medicaid Coverage.

OBJECTIVE: Examine the impact of a primary care-embedded clinical pharmacist-led intervention (UCMyRx) on hemoglobin A1C and blood pressure control, relative to usual care, among patients with Type 2 diabetes (TD2) and Medicaid, in a large healthcare system. METHODS: We used data extracted from the Electronic Health Records system and a Difference-In-Differences study design with a 2:1 propensity-matched comparison group to evaluate the impact of UCMyRx on HbA1c and systolic blood pressure among patients with TD2 and Medicaid, relative to usual care. RESULTS: Having at least one UCMyRx clinical pharmacist visit was associated with a significant reduction in HbA1c; (-.27%, P-value= .03) but no impact on SBP. We do not find differential UCMyRx effects on HbA1c or SBP among the subpopulations with baseline HbA1C ≥9% or SBP ≥150 mmHg, respectively. In Charlson Comorbidity Index (CCI)-stratified analyses we found stronger UCMyRx effects on HbA1C (-.47%, P-value< .02) among the CCI tercile with the lowest comorbidity score (CC1 ≤ 5). Significant UCMyRx effects are only observed among the subpopulation of Medicaid beneficiaries without Medicare (-.35%, P-value= .02). CONCLUSIONS: The UCMyRx intervention is a useful strategy for improving HbA1c control among patients with TD2 and Medicaid.

International comparisons of laboratory values from the 4CE collaborative to predict COVID-19 mortality.

Given the growing number of prediction algorithms developed to predict COVID-19 mortality, we evaluated the transportability of a mortality prediction algorithm using a multi-national network of healthcare systems. We predicted COVID-19 mortality using baseline commonly measured laboratory values and standard demographic and clinical covariates across healthcare systems, countries, and continents. Specifically, we trained a Cox regression model with nine measured laboratory test values, standard demographics at admission, and comorbidity burden pre-admission. These models were compared at site, country, and continent level. Of the 39,969 hospitalized patients with COVID-19 (68.6% male), 5717 (14.3%) died. In the Cox model, age, albumin, AST, creatine, CRP, and white blood cell count are most predictive of mortality. The baseline covariates are more predictive of mortality during the early days of COVID-19 hospitalization. Models trained at healthcare systems with larger cohort size largely retain good transportability performance when porting to different sites. The combination of routine laboratory test values at admission along with basic demographic features can predict mortality in patients hospitalized with COVID-19. Importantly, this potentially deployable model differs from prior work by demonstrating not only consistent performance but also reliable transportability across healthcare systems in the US and Europe, highlighting the generalizability of this model and the overall approach.

Medical conditions of primary care patients with documented cannabis use and cannabis use disorder in electronic health records: a case control study from an academic health system in a medical marijuana state.

BACKGROUND: Approximately 3.8% of adults worldwide have used cannabis in the past year. Understanding how cannabis use is associated with other health conditions is crucial for healthcare providers seeking to understand the needs of their patients, and for health policymakers. This paper analyzes the relationship between documented cannabis use disorders (CUD), cannabis use (CU) and other health diagnoses among primary care patients during a time when medical use of marijuana was permitted by state law in California, United States of America. METHODS: The study utilized primary care electronic health record (EHR) data from an academic health system, using a case-control design to compare diagnoses among individuals with CUD/CU to those of matched controls, and those of individuals with CUD diagnoses with individuals who had CU otherwise documented. Associations of documented CU and CUD with general medical conditions and health conditions associated with cannabis use (both medical and behavioral) were analyzed using conditional logistic regression. RESULTS: Of 1,047,463 patients with ambulatory encounters from 2013-2017, 729 (0.06%) had CUD diagnoses and 3,731 (0.36%) had CU documented in their EHR. Patients with documented CUD and CU patients had significantly (p < 0.01) higher odds of most medical and behavioral diagnoses analyzed. Compared to matched controls, CUD-documented patients had highest odds of other substance use disorders (OR = 21.44: 95% CI 9.43-48.73), any mental health disorder (OR = 6.99; 95% CI 5.03-9.70) social anxiety disorder (OR = 13.03; 95% CI 2.18-77.94), HIV/AIDS (OR = 7.88: 95% CI 2.58-24.08), post-traumatic stress disorder (OR = 7.74: 95% CI 2.66-22.51); depression (OR = 7.01: 95% CI 4,79-10.27), and bipolar disorder (OR = 6.49: 95% CI 2.90-14.52). Compared to matched controls, CU-documented patients had highest odds of other substance use disorders (OR = 3.64; 95% CI 2.53-5.25) and post-traumatic stress disorder (OR = 3.41; 95% CI 2.53-5.25). CUD-documented patients were significantly more likely than CU-documented patients to have HIV/AIDS (OR = 6.70; 95% CI 2.10-21.39), other substance use disorder (OR = 5.88; 95% CI 2.42-14.22), depression (OR = 2.85; 95% CI 1.90-4.26), and anxiety (OR = 2.19: 95% CI 1.57-3.05) diagnoses. CONCLUSION: The prevalence of CUD and CU notation in EHR data from an academic health system was low, highlighting the need for improved screening in primary care. CUD and CU documentation were associated with increased risk for many health conditions, with the most elevated risk for behavioral health disorders and HIV/AIDS (among CUD-documented, but not CU-documented patients). Given the strong associations of CUD and CU documentation with health problems, it is important for healthcare providers to be prepared to identify CU and CUD, discuss the pros and cons of cannabis use with patients thoughtfully and empathically, and address cannabis-related comorbidities among these patients.

Displaying Cost and Completion Time for Reference Laboratory Test Orders-A Randomized Controlled Trial.

OBJECTIVES: Reduction in unnecessary services is one strategy for increasing the value of health care. Reference laboratory, or send-out, tests are associated with considerable costs. We investigated whether displaying cost and turnaround time (TAT), or time-to-result, for reference laboratory tests at the time of order entry in the electronic health record (EHR) system would impact provider ordering practices. METHODS: Reference laboratory test cost and TAT data were randomized prior to the study and only displayed for the intervention group. A 24-month dataset composed of 12 months each for baseline and study periods was extracted from the clinical data mart. A difference-in-differences (DID) analysis was conducted using a linear mixed-effects model to estimate the association between the intervention and changes in test-ordering patterns. RESULTS: In the inpatient setting, the DIDs of aggregate test-order costs and volume were not different among the control and intervention groups (p = 0.31 and p = 0.26, respectively). In the ambulatory setting, the DIDs of aggregate test-order costs and volume were not different among the control and intervention groups (p = 0.82 and p = 0.51, respectively). For both inpatient and ambulatory settings, no significant difference was observed in the DID of aggregate test-order costs and volumes calculated in respect to stratified relative cost and TAT groups (p > 0.05). CONCLUSION: Lack of alternative tests, test orders placed at a late step in patient management, and orders facilitated by trainees or mid-level providers may have limited the efficacy of the intervention. Our randomized study demonstrated no significant association between the display of cost or TAT display and ordering frequency.

Epigenome-wide association study of bronchopulmonary dysplasia in preterm infants: results from the discovery-BPD program.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a lung disease in premature infants caused by therapeutic oxygen supplemental and characterized by impaired pulmonary development which persists into later life. While advances in neonatal care have improved survival rates of premature infants, cases of BPD have been increasing with limited therapeutic options for prevention and treatment. This study was designed to explore the relationship between gestational age (GA), birth weight, and estimated blood cell-type composition in premature infants and to elucidate early epigenetic biomarkers associated with BPD. METHODS: Cord blood DNA from preterm neonates that went on to develop BPD (n = 14) or not (non-BPD, n = 93) was applied to Illumina 450 K methylation arrays. Blood cell-type compositions were estimated using DNA methylation profiles. Multivariable robust regression analysis elucidated CpGs associated with BPD risk. cDNA microarray analysis of cord blood RNA identified differentially expressed genes in neonates who later developed BPD. RESULTS: The development of BPD and the need for oxygen supplementation were strongly associated with GA (BPD, p < 1.0E-04; O2 supplementation, p < 1.0E-09) and birth weight (BPD, p < 1.0E-02; O2 supplementation, p < 1.0E-07). The estimated nucleated red blood cell (NRBC) percent was negatively associated with birth weight and GA, positively associated with hypomethylation of the tobacco smoke exposure biomarker cg05575921, and high-NRBC blood samples displayed a hypomethylation profile. Epigenome-wide association study (EWAS) identified 38 (Bonferroni) and 275 (false discovery rate 1%) differentially methylated CpGs associated with BPD. BPD-associated CpGs in cord blood were enriched for lung maturation and hematopoiesis pathways. Stochastic epigenetic mutation burden at birth was significantly elevated among those who developed BPD (adjusted p = 0.02). Transcriptome changes in cord blood cells reflected cell cycle, development, and pulmonary disorder events in BPD. CONCLUSIONS: While results must be interpreted with caution because of the small size of this study, NRBC content strongly impacted DNA methylation profiles in preterm cord blood and EWAS analysis revealed potential insights into biological pathways involved in BPD pathogenesis.

Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey.

BACKGROUND: Polychlorinated biphenyl (PCB) exposures have been associated with liver injury in human cohorts, and steatohepatitis with liver necrosis in model systems. MicroRNAs (miRs) maintain cellular homeostasis and may regulate the response to environmental stress. OBJECTIVES: We tested the hypothesis that specific miRs are associated with liver disease and PCB exposures in a residential cohort. METHODS: Sixty-eight targeted hepatotoxicity miRs were measured in archived serum from 734 PCB-exposed participants in the cross-sectional Anniston Community Health Survey. Necrotic and other liver disease categories were defined by serum keratin 18 (K18) biomarkers. Associations were determined between exposure biomarkers (35 ortho-substituted PCB congeners) and disease biomarkers (highly expressed miRs or previously measured cytokines), and Ingenuity Pathway Analysis was performed. RESULTS: The necrotic liver disease category was associated with four up-regulated miRs (miR-99a-5p, miR-122-5p, miR-192-5p, and miR-320a) and five down-regulated miRs (let-7d-5p, miR-17-5p, miR-24-3p, miR-197-3p, and miR-221-3p). Twenty-two miRs were associated with the other liver disease category or with K18 measurements. Eleven miRs were associated with 24 PCBs, most commonly congeners with anti-estrogenic activities. Most of the exposure-associated miRs were associated with at least one serum hepatocyte death, pro-inflammatory cytokine or insulin resistance bioarker, or with both. Within each biomarker category, associations were strongest for the liver-specific miR-122-5p. Pathways of liver toxicity that were identified included inflammation/hepatitis, hyperplasia/hyperproliferation, cirrhosis, and hepatocellular carcinoma. Tumor protein p53 and tumor necrosis factor α were well integrated within the top identified networks. DISCUSSION: These results support the human hepatotoxicity of environmental PCB exposures while elucidating potential modes of PCB action. The MiR-derived liquid liver biopsy represents a promising new technique for environmental hepatology cohort studies. https://doi.org/10.1289/EHP9467.