Weill Cornell Medicine

Graphical abstract Highlights d Type III CRISPR-Cas systems produce cyclic oligoadenylates upon phage recognition d Type III-associated Cad1 hexamers are activated by cyclic oligoadenylate ligands d Activated Cad1 catalyzes the deamination of ATP to ITP d ITP accumulation is toxic to the bacterial host and prevents viral spread Correspondence pateld@mskcc.org (D.J.P.), marraffini@rockefeller.edu (L.A.M.) In brief Cad1 is an hexameric type III CRISPR-CARF effector harboring an adenosine deaminase domain that is activated by cyclic oligonucleotides produced upon phage recognition. Cad1 activation results in ATP deamination, accumulation of ITP, and a growth arrest of the infected host that prevents viral spread. SUMMARY Type III CRISPR systems provide immunity against genetic invaders through the production of cyclic oligo-adenylate (cA n) molecules that activate effector proteins that contain CRISPR-associated Rossman fold (CARF) domains. Here, we characterized the function and structure of an effector in which the CARF domain is fused to an adenosine deaminase domain, CRISPR-associated adenosine deaminase 1 (Cad1). We show that upon binding of cA 4 or cA 6 to its CARF domain, Cad1 converts ATP to ITP, both in vivo and in vitro. Cry-oelectron microscopy (cryo-EM) structural studies on full-length Cad1 reveal an hexameric assembly composed of a trimer of dimers, with bound ATP at inter-domain sites required for activity and ATP/ITP within deaminase active sites. Upon synthesis of cA n during phage infection, Cad1 activation leads to a growth arrest of the host that prevents viral propagation. Our findings reveal that CRISPR-Cas systems employ a wide range of molecular mechanisms beyond nucleic acid degradation to provide adaptive immunity in prokaryotes.

Objective Our aim was to determine the most significant barriers to total joint arthroplasty (TJA) for people living in high‐poverty communities relative to low‐poverty communities. Methods We created a 21‐question survey based on interviews with underrepresented minority patients with osteoarthritis targeting five barriers to TJA: trust in surgeon, recovery concerns, cost and/or insurance issues, fear of poor surgical outcomes, and timing considerations. Participants rated the importance of each barrier on a 5‐point Likert scale, dichotomized into “very or extremely important” and “not as important.” The survey was distributed at New York City clinics and nationally through an arthritis advocacy group. We used geocoding to link addresses to census tracts, defining high‐poverty communities as those with ≥20% of residents living below the poverty level. Logistic regression models assessed the association between community poverty status and rating barriers as very or extremely important, with adjustment for demographic and clinical factors. Results Of the 702 survey participants, 16.8% were residents of high‐poverty communities. After adjustment, participants from high‐poverty communities were more likely to rate trust in surgeon (adjusted odds ratio [aOR] 1.87, 95% confidence interval [CI] 1.24–2.82) and fear of poor surgical outcome (aOR 1.68, 95% CI 1.08–2.61) as very or extremely important. Conclusion People from high‐poverty communities identified lack of trust in surgeons and fear of poor surgical outcomes as more significant barriers to TJA compared to people from low‐poverty communities.

Background Vitamin D deficiency is linked to worse outcomes in patients with chronic liver diseases (CLD). However, data in patients with autoimmune hepatitis (AIH) remain limited. Aims We aimed to assess the impact of vitamin D deficiency on the outcomes of individuals with AIH. Methods This retrospective cohort study used the TriNetX research network to identify patients with AIH. Patients were matched using propensity score matching and stratified to sufficient vitamin D levels (e.g., 25 (OH) D3 ≥ 30 ng/mL), vitamin D insufficiency (25 (OH) D3: 20–29.9 ng/mL) and vitamin D deficiency (e.g., 25 (OH) D3 < 20 ng/mL). The primary outcome was the all‐cause mortality among adult patients with AIH. Secondary outcomes included decompensated liver cirrhosis, acute hepatic failure, liver transplantation (LT), all‐cause hospitalizations and all‐cause critical care admissions. Results A total of 1288 AIH patients with vitamin D deficiency were identified and propensity matched with 1288 patients with normal vitamin D levels. Patients with vitamin D deficiency had significantly increased odds for all‐cause mortality compared to those with normal levels (adjusted odds ratio (aOR) = 3.2, 95%CI: 2.3–4.48). Patients with vitamin D deficiency were at increased odds of all‐cause hospitalizations (aOR = 2.37, 95%CI: 1.97–2.84), critical care unit admissions (aOR = 2.8, 95%CI: 2.21–3.71), decompensated liver cirrhosis (aOR = 2.74, 95%CI: 2.13–3.54), acute hepatic failure (aOR = 3.11, 95%CI: 2.09–4.62) and LT (aOR = 3.47, 95%CI: 1.71–7.04), as compared to those with normal vitamin D levels. Conclusion This cohort study showed significantly increased odds for all‐cause mortality in AIH patients with vitamin D deficiency. Vitamin D deficiency in patients with AIH was associated with increased likelihood of hospitalisation, decompensated liver cirrhosis, acute liver failure and LT.

HIV-1 infection leads to chronic disease requiring life-long treatment and therefore alternative therapeutics, a cure and/or a protective vaccine are needed. Antibody-mediated effector functions could have a role in the fight against HIV-1. However, the properties underlying the potential beneficial effects of antibodies during HIV-1 infection are poorly understood. To identify a specific profile of antibody features associated with delayed disease progression, we studied antibody polyfunctionality during untreated HIV-1 infection in the well-documented Amsterdam Cohort Studies. Serum samples were analyzed from untreated individuals with HIV-1 at approximately 6 months (n = 166) and 3 years (n = 382) post-seroconversion (post-SC). A Luminex antibody Fc array was used to profile 15 different Fc features for serum antibodies against 20 different HIV-1 envelope glycoprotein antigens and the resulting data was also compared with data on neutralization breadth. We found that high HIV-1 specific IgG1 levels and low IgG2 and IgG4 levels at 3 years post-SC were associated with delayed disease progression. Moreover, delayed disease progression was associated with a broad and polyfunctional antibody response. Specifically, the capacity to interact with all Fc γ receptors (FcγRs) and C1q, and in particular with FcγRIIa, correlated positively with delayed disease progression. There were strong correlations between antibody Fc features and neutralization breadth and several antibody features that were associated with delayed disease progression were also associated with the development of broad and potent antibody neutralization. In summary, we identified a strong association between broad, polyfunctional antibodies and delayed disease progression. These findings contribute new information for the fight against HIV-1, especially for new antibody-based therapy and cure strategies.

BACKGROUND Cardiac allograft vasculopathy (CAV) leads to impaired myocardial blood flow (MBF), increasing the risk of cardiovascular death or retransplant among heart transplantation (HT) recipients. Data on elevation in donor-derived cell-free DNA (dd-cfDNA) and CAV in the absence of rejection are mixed. We sought to test the hypothesis that CAV with reduced MBF (RMBF) is associated with elevated dd-cfDNA. METHODS A retrospective review was conducted on HT recipients at a high-volume center who underwent dd-cfDNA testing between September 2019 and November 2022. Inclusion criteria included undergoing CAV screening with cardiac positron emission tomography scans and coronary angiograms. Patients were grouped by the presence of angiographic CAV diagnosis and MBF reserve evaluated through cardiac positron emission tomography. The latter was subdivided into normal MBF or RMBF, with RMBF defined as an MBF reserve ≤2. Elevated dd-cfDNA was defined as ≥0.12%. RESULTS Two hundred fifty-six HT recipients were included (median age, 55 years; 27.6% female; median, 8 years [interquartile range (IQR), 5–14] post-HT). Ischemic etiology of heart failure was more prevalent in the RMBF group (36%) compared with the normal MBF group (20%; P =0.02). The prevalence and magnitude of a positive dd-cfDNA test with angiographic CAV (29%; median, 0.26% [IQR, 0.15%–0.62%]) were not significantly different from those without CAV (30%; P =0.94; median, 0.31% [IQR, 0.17%–0.71%]; P =0.38). However, RMBF patients exhibited significantly higher dd-cfDNA prevalence and levels (51%; median, 0.81% [IQR, 0.48%–1.11%]) compared with normal MBF patients (27%; P <0.001; median, 0.25% [IQR, 0.15%–0.52%]; P <0.001). CONCLUSIONS HT recipients with angiographic CAV had similar dd-cfDNA levels and rates as those without. Notably, dd-cfDNA levels and rates were significantly elevated in patients with RMBF assessed by positron emission tomography compared with those with normal MBF.

Objectives To evaluate the association between cardiorespiratory fitness (CRF) and cognition in a large sample of older adults, and to examine clinical and demographic factors that might moderate these associations. Methods CRF was measured with a graded exercise test performed on a motorised treadmill. A confirmatory factor analysis was conducted using data from a comprehensive neuropsychological battery to obtain latent factors reflecting core cognitive domains. Linear regression models evaluated the association between CRF and each of the cognitive composites, and potential moderators including demographic factors (age, sex, education), apolipoprotein E ε4 ( APOE4 ) carriage, beta-blocker use and components of maximal effort criteria during CRF testing. Results The sample consisted of 648 adults (mean (SD) age 69.88 (3.75)), including 461 women (71.1%). The highest oxygen consumption obtained during testing (VO 2max ) was mean (SD) = 21.68 (5.06) mL/kg/min. We derived a five-factor model composed of episodic memory, processing speed, working memory, executive function/attentional control and visuospatial function. Higher CRF was associated with better performance across all five cognitive domains after controlling for covariates. Age and APOE4 carriage did not moderate observed associations. The relationship between CRF and cognitive performance was greater in women, those with fewer years of education and those taking beta-blockers in the domains of processing speed (sex: β=−0.447; p=0.015; education: β=−0.863; p=0.018) and executive function/attentional control (sex: β=−0.417; p=0.022; education β=−0.759; p=0.034; beta-blocker use: β=0.305; p=0.047). Conclusion Higher CRF in older adulthood is associated with better cognitive performance across multiple domains susceptible to age-related cognitive decline. Sex, education and use of beta-blockers moderated observed associations within select cognitive domains.

Study Objective Traumatic brain injury (TBI) during early childhood (before 6 years) is prevalent, accounting for rising rates of emergency department visits. These injuries may lead to postconcussive symptoms, which may be subtle and difficult to diagnose in young children. Inadequate discharge counseling may lead to prolonged duration of symptoms and possible developmental delays. We aimed to explore pediatric emergency medicine (PEM) physicians' perspectives on “concussion” terminology, diagnosis, and management, specifically in a young child with mild TBI. Methods We conducted semistructured interviews using open-ended questions involving a hypothetical scenario. We recruited currently practicing PEM physicians by a snowball sampling method. A research team recorded, transcribed, and analyzed the interviews. Using social constructionism as the philosophical framework, we developed and refined codes and derived themes until reaching thematic saturation. Peer debriefing with an expert collaborator aided with revisions of themes. Results A single PEM researcher interviewed 13 participants. Three primary themes emerged. Our first theme identified the role of guidelines and tools in the diagnostic workup. Most participants utilized a clinical prediction tool for neuroimaging but no clinical symptom scales. Our second theme described the difficulties and inconsistencies in the approach to diagnosis of concussion, largely due to young age, lack of verbal skills and unreliable examinations. Our last theme focused on the difficulty in providing clear discharge instructions to parents. Many participants described difficulty providing activity restrictions, instead allowing self-modulation, and lack of counseling for educational tasks. Conclusions Variability exists among PEM physicians in diagnosis and management of concussions in young children. Discomfort with lack of reliability of symptoms and underappreciation of typical early childhood characteristics may account for findings. Educational initiatives, age-appropriate clinical tools and treatment-guided outcomes research are needed to guide PEM physicians in the care of young children with head injuries.

Background The existence of sociodemographic disparities in pancreatic cancer has been well‐studied but how these disparities have changed over time is unclear. The purpose of this study was to longitudinally assess patient management in the context of sociodemographic factors to identify persisting disparities in pancreatic cancer care. Methods Using the National Cancer Database, patients diagnosed with pancreatic ductal adenocarcinoma from 2010 to 2017 were identified. The primary outcomes were surgical resection and/or receipt of chemotherapy. Outcome measures included changes in associations between sociodemographic factors (i.e., sex, age, race, comorbidity index, SES, and insurance type) and treatment‐related factors (i.e., clinical stage at diagnosis, surgical resection, and receipt of chemotherapy). For each year, associations were assessed via univariate and multivariate analyses. Results Of 75,801 studied patients, the majority were female (51%), White (83%), and had government insurance (65%). Older age (range of OR 2010–2017 [range‐OR]:0.19–0.29), Black race (range‐OR: 0.61–0.78), lower SES (range‐OR: 0.52–0.94), and uninsured status (range‐OR: 0.46–0.71) were associated with lower odds of surgical resection (all p < 0.005), with minimal fluctuations over the study period. Older age (range‐OR: 0.11–0.84), lower SES (range‐OR: 0.41–0.63), and uninsured status (range‐OR: 0.38–0.61) were associated with largely stable lower odds of receiving chemotherapy (all p < 0.005). Conclusions Throughout the study period, age, SES, and insurance type were associated with stable lower odds for both surgery and chemotherapy. Black patients exhibited stable lower odds of resection underscoring the continued importance of mitigating racial disparities in surgery. Investigation of mechanisms driving sociodemographic disparities are needed to promote equitable care.

Background Sarcomatoid (and rhabdoid) dedifferentiation can occur in ∼5% of renal cell carcinomas (sRCC), a finding with significant therapeutic implications. sRCC is associated with increased aggressiveness, resistance to conventional targeted therapies, and increased sensitivity to immune checkpoint inhibitors. Objective There are no preclinical models for sRCC that can be used in research to better understand this disease. The pig has similar size, anatomy, immune system, and genetics, that can be employed to evaluate procedures or tumor specific drugs. We report on the creation of a large animal porcine model for sRCC. Materials In eight Oncopigs, a Cre-recombinase gene adenoviral vector (AdCre) was incubated with renal tissue obtained from an ultrasound (US) percutaneous biopsy and reinjected into the renal cortex. US was performed to assess growth and to obtain tumor tissue for pathologic and immunohistochemistry evaluation. Results Three weeks post inoculation renal tumors were successfully formed in 28 out of 32 sites (88%). Mean tumor size by imaging was 1.6 × 1.1 cm (range: 0.4–3.9 cm longest axis). Pigs remained clinically healthy up to 25 days after inoculation. On histology, tumors consisted of foci of infiltrating sarcomatoid and rhabdoid cells in a background of marked acute and chronic inflammation. The neoplastic cells showed positive immunoreactivity for PAX8, cytokeratin AE1/AE3 supporting a renal tubular origin. These cells were diffusely positive for p53 and showed high ki-67 (20–30%), and cleaved caspase 3 (20–30%) expression. Conclusion Rapid growing poorly differentiated neoplasms associated with a marked inflammatory reaction that have phenotypic and immunohistochemical features of sRCC were successfully developed. These may be suitable to study the response to local and systemic therapies.

INTRODUCTION Blood‐based biomarkers (BBMs) can enable early detection of brain amyloid beta (Aβ) pathology in cognitively unimpaired individuals. However, the extent to which common medical conditions affect biomarker performance remains unclear. METHODS Participants (n = 348) included individuals without cognitive impairment. We studied how brain Aβ associated with BBMs (Aβ42/40, phosphorylated tau [p‐tau] 181 and 217, p‐tau217/Aβ42, glial fibrillary acidic protein [GFAP], and neurofilament light [NfL]) and optimal BBM thresholds for predicting brain Aβ positivity and whether they are obscured by the presence of common medical conditions. RESULTS Plasma Aβ42/40, p‐tau181, p‐tau217, and GFAP, but not NfL, were significantly associated with brain Aβ. P‐tau217/Aβ42 showed the best discriminative performance (area under the curve: 0.91). The strength of p‐tau217–brain Aβ associations were obscured by diabetes and cardiovascular conditions. DISCUSSION These results suggest BBMs may help detect early Aβ pathology but suggest caution in their use due to common medical conditions that could affect accuracy. Highlights Plasma Aβ42/40, p‐tau181, p‐tau217, and GFAP but not NfL showed significant associations with brain Aβ. BBMs were more strongly associated with the level of brain Aβ in those without diabetes and cardiovascular conditions. P‐tau217/Aβ42 showed the best performance (AUC = 0.91) in discriminating Aβ presence with an optimal cut‐off of >1.2, followed by p‐tau217 at >0.46 pg/mL, with performance slightly improving when excluding participants with cardiovascular conditions.

INTRODUCTION The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is evaluating lifestyle interventions in older adults at risk for cognitive decline and dementia. Here we characterize the baseline data set of the POINTER Imaging ancillary study. METHODS Participants underwent health and cognitive assessments and neuroimaging with multimodal positron emission tomography (PET) (beta‐amyloid [Aβ] and tau) and magnetic resonance imaging (MRI). Framingham risk score (FRS) was used to quantify cardiovascular disease (CVD) risk. RESULTS A total of 1052 participants (31% from underrepresented ethnoracial groups) were enrolled. Compared to Aβ−, Aβ+ (29%) participants were older, had higher apolipoprotein E (APOE) ε4 carriage rate and white matter hyperintensity volume, and greater temporal tau. FRS was related to MRI measures, but not AD biomarkers. FRS and tau had independent effects on cognition. DISCUSSION In this heterogenous, at‐risk cohort, CVD risk was related to more abnormal brain structure and poorer cognition, representing a putative non‐AD (Alzheimer's disease) pathway to brain injury and cognitive decline. Highlights ·The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort is enriched for cardiovascular disease (CVD) and poor lifestyle ·POINTER Imaging collected multimodal neuroimaging data in this unique, at‐risk cohort ·Amyloid burden was related to age, apolipoprotein E (APOE) ε4 carriage, and measures of disease progression ·Associations between amyloid and tau, and tau and cognition, were relatively weak ·CVD risk and tau pathology were independently related to memory

Purpose To develop a breath‐hold cardiac quantitative susceptibility mapping (QSM) sequence for noninvasive measurement of differential cardiac chamber blood oxygen saturation (ΔSO2). Methods A non‐gated three‐dimensional stack‐of‐spirals QSM sequence was implemented to continuously sample the data throughout the cardiac cycle. Measurements of ΔSO2 between the right and left heart chamber obtained by the proposed sequence and a previously validated navigator Cartesian QSM sequence were compared in three cohorts consisting of healthy volunteers, coronavirus disease 2019 survivors, and patients with pulmonary hypertension. In the pulmonary‐hypertension cohort, Bland–Altman plots were used to assess the agreement of ΔSO2 values obtained by QSM and those obtained by invasive right heart catheterization (RHC). Results Compared with navigator QSM (average acquisition time 419 ± 158 s), spiral QSM reduced the scan time on average by over 20‐fold to a 20‐s breath‐hold. In all three cohorts, spiral QSM and navigator QSM yielded similar ΔSO2. Among healthy volunteers and coronavirus disease 2019 survivors, ΔSO2 was 17.41 ± 4.35% versus 17.67 ± 4.09% for spiral and navigator QSM, respectively. In pulmonary‐hypertension patients, spiral QSM showed a slightly smaller ΔSO2 bias and narrower 95% limits of agreement than that obtained by navigator QSM (1.09% ± 6.47% vs. 2.79% ± 6.99%) when compared with right heart catheterization. Conclusion Breath‐hold three‐dimensional spiral cardiac QSM for measuring differential cardiac chamber blood oxygenation is feasible and provides values in good agreement with navigator cardiac QSM and with reference right heart catheterization.

Background Previous studies have reported a protective effect of type 2 diabetes on the incidence and progression of aortic aneurysms. We investigated whether this protective effect extends to aortic dissections. Methods Data from the US Nationwide Readmission Database (2016–2019) were analyzed. Patients admitted for open surgery repair of acute type A aortic dissection (TAAD) were initially analyzed (index group). Those discharged alive were followed for up to 30 days (readmission group). The co-primary outcomes were in-hospital and 30-day mortality. Results Between 2016 and 2019, 7,324 patients were admitted for open surgical repair of acute TAAD, of whom 965 (13.2%) had diabetes. Patients with diabetes were older and had a higher prevalence of obesity, hypertension, smoking, dyslipidemia, and chronic kidney disease (CKD). 15.2% of patients with diabetes and 14.6% without diabetes died; hence, diabetes did not have a significant impact on in-hospital mortality (adjusted odd ratio [aOR] = 1.02 [0.84–1.24]). Similarly, diabetes was not associated with a higher adjusted risk of atrial fibrillation (aOR = 1.03 [0.89–1.20]), stroke (aOR = 0.83 [0.55–1.26]), cardiogenic shock (aOR = 1.18 [0.98–1.42]), but increased the risk of acute renal failure (aOR = 1.20 [1.04–1.39]). Within 30 days of discharge, 154 (15.9%) patients with diabetes and 952 (15%) from the non-diabetes group were readmitted. Readmitted patients with diabetes were older and had a higher prevalence of cardiovascular comorbidities. We didn’t observe any significant difference in the adjusted risk of 30-day mortality between the diabetes and non-diabetes groups (adjusted hazard ratio [aHR] = 0.81 [0.41–1.60]). However, diabetes was associated with a lower risk of readmission (aHR = 0.81 [0.68–0.97]). Age was the most significant predictor of all outcomes. CKD was the most significant predictor of 30-day mortality, with the risk increasing five-fold in patients with diabetes (HR = 5.58 [2.58–6.62]. Cardiovascular-related conditions were the most common causes of readmission in both groups. However, respiratory-related conditions were more prevalent in the diabetes group compared to the non-diabetes group (19.5% vs. 13%, respectively, p = 0.032). Conclusions Diabetes does not increase in-hospital or short-term mortality in patients undergoing surgical repair for Type A aortic dissection. Graphical abstract

Purpose To develop a deep learning–based method for robust and rapid estimation of the fatty acid composition (FAC) in mammary adipose tissue. Methods A physics‐based unsupervised deep learning network for estimation of fatty acid composition‐network (FAC‐Net) is proposed to estimate the number of double bonds and number of methylene‐interrupted double bonds from multi‐echo bipolar gradient‐echo data, which are subsequently converted to saturated, mono‐unsaturated, and poly‐unsaturated fatty acids. The loss function was based on a 10 fat peak signal model. The proposed network was tested with a phantom containing eight oils with different FAC and on post‐menopausal women scanned using a whole‐body 3T MRI system between February 2022 and January 2024. The post‐menopausal women included a control group (n = 8) with average risk for breast cancer and a cancer group (n = 7) with biopsy‐proven breast cancer. Results The FAC values of eight oils in the phantom showed strong correlations between the measured and reference values (R² > 0.9 except chain length). The FAC values measured from scan and rescan data of the control group showed no significant difference between the two scans. The FAC measurements of the cancer group conducted before contrast and after contrast showed a significant difference in saturated fatty acid and mono‐unsaturated fatty acid. The cancer group has higher saturated fatty acid than the control group, although not statistically significant. Conclusion The results in this study suggest that the proposed FAC‐Net can be used to measure the FAC of mammary adipose tissue from gradient‐echo MRI data of the breast.

Background Surgical planning for orthognathic procedures demands swift and accurate biomechanical modeling of facial soft tissues. Efficient simulations are vital in the clinical pipeline, as surgeons may iterate through multiple plans. Biomechanical simulations typically use the finite element method (FEM). Prior works divide FEM simulations into increments to enhance convergence and accuracy. However, this practice elongates simulation time, thereby impeding clinical integration. To accelerate simulations, deep learning (DL) models have been explored. Yet, previous efforts either perform simulations in a single step or neglect the temporal aspects in incremental simulations. Purpose This study investigates the use of spatiotemporal incremental modeling for biomechanics simulations of facial soft tissue. Methods We implement the method using a graph neural network. Our method synergizes spatial features with temporal aggregation using DL networks trained on incremental FEM simulations from 17 subjects that underwent orthognathic surgery. Results Our proposed spatiotemporal incremental method achieved a mean accuracy of 0.37 mm with a mean computation time of 1.52 s. In comparison, a spatial‐only incremental method yielded a mean accuracy of 0.44 mm and a mean computation time of 1.60 s, while a spatial‐only single‐step method yielded a mean accuracy of 0.41 mm and a mean computation time of 0.05 s. Conclusions Statistical analysis demonstrated that the spatiotemporal incremental method reduced mean errors compared to the spatial‐only incremental method, emphasizing the importance of incorporating temporal information in incremental simulations. Overall, we successfully implemented spatiotemporal incremental learning tailored to simulate soft tissue deformation while substantially reducing simulation time compared to FEM.

Importance Understanding whether there are racial and ethnic and residential disparities in prenatal telehealth uptake is necessary for ensuring equitable access and guiding implementation of future hybrid (ie, both telehealth and in-person) prenatal care. Objective To assess temporal changes in individuals using hybrid prenatal care before and during the COVID-19 public health emergency (PHE) by race and ethnicity and residence location in the US. Design, Setting, and Participants This retrospective cohort study analyzed electronic health record data of prenatal care visits from the National COVID Cohort Collaborative Data Enclave, comprising data from 75 health systems and freestanding institutes in all 50 US states. Data were analyzed on 349 682 nationwide pregnancies among 349 524 people who gave birth from June 1, 2018, through May 31, 2022. Multivariable generalized estimating equations were used to examine variations in receiving hybrid vs only in-person prenatal care. Data phenotyping and analysis occurred from June 13, 2023, to September 27, 2024. Exposures Prenatal period overlap (never, partially, or fully overlapping) with the COVID-19 PHE, maternal race and ethnicity, and urban or rural residence. Main Outcomes and Measures Hybrid vs in-person–only prenatal care. Results Of 349 682 pregnancies (mean [SD] age, 29.4 [5.9] years), 59 837 (17.1%) were in Hispanic or Latino individuals, 14 803 (4.2%) in non-Hispanic Asian individuals, 65 571 (18.8%) in non-Hispanic Black individuals, 162 677 (46.5%) in non-Hispanic White individuals, and 46 794 (13.4%) in non-Hispanic individuals from other racial and ethnic groups. A total of 31 011 participants (8.9%) resided in rural communities. Hybrid prenatal care increased from nearly none before March 2020 to a peak of 8.1% telehealth visits in November 2020, decreasing slightly to 6.2% by March 2022. Among the fully overlapping group, urban residents had nearly 2-fold odds of hybrid prenatal care compared with rural people (adjusted odds ratio [AOR], 1.98; 95% CI, 1.84-2.12). Hispanic or Latino people (AOR, 1.48; 95% CI, 1.41-1.56), non-Hispanic Asian people (AOR, 1.47; 95% CI, 1.35-1.59), and non-Hispanic Black people (AOR, 1.18; 95% CI, 1.12-1.24) were more likely to receive hybrid prenatal care than non-Hispanic White people. Conclusions and Relevance In this cohort study, hybrid prenatal care increased substantially during the COVID-19 PHE, but pregnant people living in rural areas had lower levels of hybrid care than urban people, and individuals who belonged to racial and ethnic minority groups were more likely to have hybrid care than White individuals. These findings suggest that strategies that improve equitable access to telehealth for people who live in rural areas and people in some minority racial and ethnic groups may be useful.