ZAP-70 in Signaling, Biology, and Disease.

T cells possess an array of functional capabilities important for host defense against pathogens and tumors. T cell effector functions require the T cell antigen receptor (TCR). The TCR has no intrinsic enzymatic activity, and thus signal transduction from the receptor relies on additional signaling molecules. One such molecule is the cytoplasmic tyrosine kinase ZAP-70, which associates with the TCR complex and is required for initiating the canonical biochemical signal pathways downstream of the TCR. In this article, we describe recent structure-based insights into the regulation and substrate specificity of ZAP-70, and then we review novel methods for determining the role of ZAP-70 catalytic activity-dependent and -independent signals in developing and mature T cells. Lastly, we discuss the disease states in mouse models and humans, which range from immunodeficiency to autoimmunity, that are caused by mutations in ZAP-70.

TCR signaling promotes formation of an STS1-Cbl-b complex with pH-sensitive phosphatase activity that suppresses T cell function in acidic environments.

T cell responses are inhibited by acidic environments. T cell receptor (TCR)-induced protein phosphorylation is negatively regulated by dephosphorylation and/or ubiquitination, but the mechanisms underlying sensitivity to acidic environments are not fully understood. Here, we found that TCR stimulation induced a molecular complex of Cbl-b, an E3-ubiquitin ligase, with STS1, a pH-sensitive unconventional phosphatase. The induced interaction depended upon a proline motif in Cbl-b interacting with the STS1 SH3 domain. STS1 dephosphorylated Cbl-b interacting phosphoproteins. The deficiency of STS1 or Cbl-b diminished the sensitivity of T cell responses to the inhibitory effects of acid in an autocrine or paracrine manner in vitro or in vivo. Moreover, the deficiency of STS1 or Cbl-b promoted T cell proliferative and differentiation activities in vivo and inhibited tumor growth, prolonged survival, and improved T cell fitness in tumor models. Thus, a TCR-induced STS1-Cbl-b complex senses intra- or extra-cellular acidity and regulates T cell responses, presenting a potential therapeutic target for improving anti-tumor immunity.

Slow phosphorylation of a tyrosine residue in LAT optimizes T cell ligand discrimination.

Self-non-self discrimination is central to T cell-mediated immunity. The kinetic proofreading model can explain T cell antigen receptor (TCR) ligand discrimination; however, the rate-limiting steps have not been identified. Here, we show that tyrosine phosphorylation of the T cell adapter protein LAT at position Y132 is a critical kinetic bottleneck for ligand discrimination. LAT phosphorylation at Y132, mediated by the kinase ZAP-70, leads to the recruitment and activation of phospholipase C-γ1 (PLC-γ1), an important effector molecule for T cell activation. The slow phosphorylation of Y132, relative to other phosphosites on LAT, is governed by a preceding glycine residue (G131) but can be accelerated by substituting this glycine with aspartate or glutamate. Acceleration of Y132 phosphorylation increases the speed and magnitude of PLC-γ1 activation and enhances T cell sensitivity to weaker stimuli, including weak agonists and self-peptides. These observations suggest that the slow phosphorylation of Y132 acts as a proofreading step to facilitate T cell ligand discrimination.

Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT.

T cell-antigen receptor (TCR) signaling requires the sequential activities of the kinases Lck and Zap70. Upon TCR stimulation, Lck phosphorylates the TCR, thus leading to the recruitment, phosphorylation, and activation of Zap70. Lck binds and stabilizes phosho-Zap70 by using its SH2 domain, and Zap70 phosphorylates the critical adaptors LAT and SLP76, which coordinate downstream signaling. It is unclear whether phosphorylation of these adaptors occurs through passive diffusion or active recruitment. We report the discovery of a conserved proline-rich motif in LAT that mediates efficient LAT phosphorylation. Lck associates with this motif via its SH3 domain, and with phospho-Zap70 via its SH2 domain, thereby acting as a molecular bridge that facilitates the colocalization of Zap70 and LAT. Elimination of this proline-rich motif compromises TCR signaling and T cell development. These results demonstrate the remarkable multifunctionality of Lck, wherein each of its domains has evolved to orchestrate a distinct step in TCR signaling.

Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade.

The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here, we identify induction of glucocorticoid receptor (GR) expression as a common feature of drug-resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance, whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure.

Nanosecond solvation dynamics in a polymer electrolyte for lithium batteries.

Solvation dynamics critically affect charge transport. Spectroscopic experiments and computer simulations show that these dynamics in aqueous systems occur on a picosecond timescale. In the case of organic electrolytes, however, conflicting values ranging from 1 to several 100 picoseconds have been reported. We resolve this conflict by studying mixtures of an organic polymer and a lithium salt. Lithium ions coordinate with multiple polymer chains, resulting in temporary crosslinks. Relaxation of these crosslinks, detected by quasielastic neutron scattering, are directly related to solvation dynamics. Simulations reveal a broad spectrum of relaxation times. The average timescale for solvation dynamics in both experiment and simulation is one nanosecond. We present the direct measurement of ultraslow dynamics of solvation shell break-up in an electrolyte.

Inhibition of EZH2 transactivation function sensitizes solid tumors to genotoxic stress.

Drugs that block the activity of the methyltransferase EZH2 are in clinical development for the treatment of non-Hodgkin lymphomas harboring EZH2 gain-of-function mutations that enhance its polycomb repressive function. We have previously reported that EZH2 can act as a transcriptional activator in castration-resistant prostate cancer (CRPC). Now we show that EZH2 inhibitors can also block the transactivation activity of EZH2 and inhibit the growth of CRPC cells. Gene expression and epigenomics profiling of cells treated with EZH2 inhibitors demonstrated that in addition to derepressing gene expression, these compounds also robustly down-regulate a set of DNA damage repair (DDR) genes, especially those involved in the base excision repair (BER) pathway. Methylation of the pioneer factor FOXA1 by EZH2 contributes to the activation of these genes, and interaction with the transcriptional coactivator P300 via the transactivation domain on EZH2 directly turns on the transcription. In addition, CRISPR-Cas9-mediated knockout screens in the presence of EZH2 inhibitors identified these BER genes as the determinants that underlie the growth-inhibitory effect of EZH2 inhibitors. Interrogation of public data from diverse types of solid tumors expressing wild-type EZH2 demonstrated that expression of DDR genes is significantly correlated with EZH2 dependency and cellular sensitivity to EZH2 inhibitors. Consistent with these findings, treatment of CRPC cells with EZH2 inhibitors dramatically enhances their sensitivity to genotoxic stress. These studies reveal a previously unappreciated mechanism of action of EZH2 inhibitors and provide a mechanistic basis for potential combination cancer therapies.

Photocatalytic Activation of Aryl(trifluoromethyl) Diazos to Carbenes for High-Resolution Protein Labeling with Red Light.

State-of-the-art methods in photoproximity labeling center on the targeted generation and capture of short-lived reactive intermediates to provide a snapshot of local protein environments. Diazirines are the current gold standard for high-resolution proximity labeling, generating short-lived aryl(trifluoromethyl) carbenes. Here, we present a method to access aryl(trifluoromethyl) carbenes from a stable diazo source via tissue-penetrable, deep red to near-infrared light (600-800 nm). The operative mechanism of this activation involves Dexter energy transfer from photoexcited osmium(II) photocatalysts to the diazo, thus revealing an aryl(trifluoromethyl) carbene. The labeling preferences of the diazo probe with amino acids are studied, showing high reactivity toward heteroatom-H bonds. Upon the synthesis of a biotinylated diazo probe, labeling studies are conducted on native proteins as well as proteins conjugated to the Os photocatalyst. Finally, we demonstrate that the conjugation of a protein inhibitor to the photocatalyst also enables selective protein labeling in the presence of spectator proteins and achieves specific labeling of a membrane protein on the surface of mammalian cells via a two-antibody photocatalytic system.

Treatment of Symptomatic Carotid Webs: A Single-Center Review.

BACKGROUND: Carotid webs are abnormal thin shelf-like or flap-like tissue in the carotid bulb (proximal internal carotid artery). Rarely are carotid webs detected prior to symptoms since routine carotid artery surveillance is not performed in younger individuals without traditional risk factors for carotid disease. The cause and natural history remain unknown. In general, they are not common but should be considered in the differential diagnosis of a patient who presents with ischemic neurologic symptoms. The web can create a flow disturbance, potentiating local thrombus formation, which can embolize producing resulting in cerebral ischemia. Current treatment is to reduce thrombus formation (antithrombotics and/or anticoagulation) or to alter the flow disturbance caused by the web (surgical removal or stent). METHODS: We retrospectively identified all patients presenting with acute ischemic stroke to our Comprehensive Stroke Center that were diagnosed with carotid web from January 2020 to December 2023. Patient demographics, presentation, hospital course including treatment and complications were collected and reported. RESULTS: Fifteen patients presented with carotid web and stroke from 2020 to 2023 and 13 underwent carotid artery stenting or endarterectomy with no periprocedural complications. Most (40%) carotid webs were not primarily identified by the initial radiology interpretation. CONCLUSIONS: We discuss our experience of carotid web and its management as well as review of the current literature.

Digital health's influence on the association between birth preference and vaginal birth.

BACKGROUND: Women's preferred mode of birth during pregnancy is predictive of their actual mode of birth. Digital prenatal care services are a promising method for educating women on mode of birth to reduce elective cesareans. This study aimed to evaluate the influence of digital health on the association between birth preference and mode of birth. METHODS: Data come from 5409 pregnant women enrolled in a digital platform for women's and family health. Multi-trajectory modeling identified trajectories of digital health usage throughout pregnancy. Adjusted logistic regression models tested associations between birth preferences and mode of birth. The modifying effect of digital health usage on the association between birth preference and mode of birth was assessed on the multiplicative scale. RESULTS: Four distinct trajectories of digital service usage were identified and labeled as: (1) baseline users (52%): the reference group; (2) just-in timers (16%): high usage during the third trimester; (3) learners (26%): high educational resource usage (e.g., articles and classes) throughout pregnancy; and (4) super users (6%): high usage of both education and care resources throughout pregnancy. Overall, preferred mode of birth at enrollment was predictive of actual mode of birth; however, digital health usage moderated this association, whereby super users and learners who preferred a cesarean at enrollment were more likely to deliver vaginally, compared to baseline users who preferred a cesarean. CONCLUSION: For the increasing proportion of women considering an elective cesarean, education through a prenatal digital health platform may help to encourage vaginal birth and reduce cesarean births.

Reclaiming narratives of empowerment around Black maternal health: a strengths-based, community-informed focus group study.

OBJECTIVES: Research on Black maternal populations often focuses on deficits that can reinforce biases against Black individuals and communities. The research landscape must shift towards a strengths-based approach focused on the protective assets of Black individuals and communities to counteract bias. This study engaged the local Black community using a strengths-based approach to discuss the assets of Black maternal populations and to inform the design of a future clinical trial focused on reducing Black maternal health disparities. DESIGN: Guided by the Theory of Maternal Adaptive Capacity, we conducted three purposive focus group sessions with Black adult community members. The focus groups were semi-structured to cover specific topics, including the strengths of the local community, strengths specific to pregnant community members, how the strengths of community members can support pregnant individuals, and how the strengths of pregnant community members can facilitate a healthy pregnancy. The focus group interviews were transcribed verbatim and analyzed using thematic content analysis. RESULTS: Three focus group sessions were conducted with sixteen female individuals identifying as Black or African American. Central themes include (1) the power of pregnancy and motherhood in Black women, (2) challenging negative perceptions and media representation of Black mothers, (3) recognizing history and reclaiming cultural traditions surrounding birth, and (4) community as the foundation of Black motherhood. CONCLUSION: Black community members identified powerful themes on Black maternal health through a strengths-based lens. These focus groups fostered relationships with the Black community, elucidated possible solutions to improve Black women's health and wellness, and offered direction on our research design and intervention.

Modular Synthesis of Unnatural Peptides via Rh(III)-Catalyzed Diastereoselective Three-Component Carboamidation Reaction.

Herein we report a modular peptide ligation methodology that couples dioxazolones, arylboronic acids, and acrylamides to construct amide bonds in a diastereoselective manner under mild conditions, facilitated by Rh(III) catalysis. By converting the C-terminus of one peptide into a dioxazolone and the N-terminus of a second peptide into an acrylamide, the two pieces can be bridged by an arylboronic acid to construct unnatural phenylalanine, tyrosine, and tryptophan residues at the junction point with diastereoselectivity for their corresponding d-stereocenters. The reaction exhibits excellent functional group tolerance with a large substrate scope and is compatible with a wide array of protected amino acid residues that are utilized in Fmoc solid phase peptide synthesis. The methodology is applied to the synthesis of six diastereomeric proteasome inhibitor analogs, as well as the ligation of two 10-mer oligopeptides to construct a 21-mer polypeptide with an unnatural phenylalanine residue at the center.

Mapping the Chemical Space of Active-Site Targeted Covalent Ligands for Protein Tyrosine Phosphatases.

Protein tyrosine phosphatases (PTPs) are an important class of enzymes that modulate essential cellular processes through protein dephosphorylation and are dysregulated in various disease states. There is demand for new compounds that target the active sites of these enzymes, for use as chemical tools to dissect their biological roles or as leads for the development of new therapeutics. In this study, we explore an array of electrophiles and fragment scaffolds to investigate the required chemical parameters for covalent inhibition of tyrosine phosphatases. Our analysis juxtaposes the intrinsic electrophilicity of these compounds with their potency against several classical PTPs, revealing chemotypes that inhibit tyrosine phosphatases while minimizing excessive, potentially non-specific reactivity. We also assess sequence divergence at key residues in PTPs to explain their differential susceptibility to covalent inhibition. We anticipate that our study will inspire new strategies to develop covalent probes and inhibitors for tyrosine phosphatases.

The use of machine learning and artificial intelligence within pediatric critical care.

The field of pediatric critical care has been hampered in the era of precision medicine by our inability to accurately define and subclassify disease phenotypes. This has been caused by heterogeneity across age groups that further challenges the ability to perform randomized controlled trials in pediatrics. One approach to overcome these inherent challenges include the use of machine learning algorithms that can assist in generating more meaningful interpretations from clinical data. This review summarizes machine learning and artificial intelligence techniques that are currently in use for clinical data modeling with relevance to pediatric critical care. Focus has been placed on the differences between techniques and the role of each in the clinical arena. The various forms of clinical decision support that utilize machine learning are also described. We review the applications and limitations of machine learning techniques to empower clinicians to make informed decisions at the bedside. IMPACT: Critical care units generate large amounts of under-utilized data that can be processed through artificial intelligence. This review summarizes the machine learning and artificial intelligence techniques currently being used to process clinical data. The review highlights the applications and limitations of these techniques within a clinical context to aid providers in making more informed decisions at the bedside.

ERF mutations reveal a balance of ETS factors controlling prostate oncogenesis.

Half of all prostate cancers are caused by the TMPRSS2-ERG gene-fusion, which enables androgens to drive expression of the normally silent E26 transformation-specific (ETS) transcription factor ERG in prostate cells. Recent genomic landscape studies of such cancers have reported recurrent point mutations and focal deletions of another ETS member, the ETS2 repressor factor ERF. Here we show these ERF mutations cause decreased protein stability and mostly occur in tumours without ERG upregulation. ERF loss recapitulates the morphological and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor transcriptional repertoire, and ERF has tumour suppressor activity in the same genetic background of Pten loss that yields oncogenic activity by ERG. In the more common scenario of ERG upregulation, chromatin immunoprecipitation followed by sequencing indicates that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites both in normal and in cancerous prostate cells. Consistent with a competition model, ERF overexpression blocks ERG-dependent tumour growth, and ERF loss rescues TMPRSS2-ERG-positive prostate cancer cells from ERG dependency. Collectively, these data provide evidence that the oncogenicity of ERG is mediated, in part, by competition with ERF and they raise the larger question of whether other gain-of-function oncogenic transcription factors might also inactivate endogenous tumour suppressors.

Early Changes in Arterial Partial Pressure of Carbon Dioxide and Blood Pressure After Starting Extracorporeal Membrane Oxygenation in Children: Extracorporeal Life Support Organization Database Study of Neurologic Complications.

OBJECTIVE: Neurologic complications in pediatric patients supported by extracorporeal membrane oxygenation (ECMO) are common and lead to morbidity and mortality; however, few modifiable factors are known. DESIGN: Retrospective study of the Extracorporeal Life Support Organization registry (2010-2019). SETTING: Multicenter international database. PATIENTS: Pediatric patients receiving ECMO (2010-2019) for all indications and any mode of support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We investigated if early relative change in Pa co2 or mean arterial blood pressure (MAP) soon after starting ECMO was associated with neurologic complications. The primary outcome of neurologic complications was defined as a report of seizures, central nervous system infarction or hemorrhage, or brain death. All-cause mortality (including brain death) was used as a secondary outcome.Out of 7,270 patients, 15.6% had neurologic complications. Neurologic complications increased when the relative Pa co2 decreased by greater than 50% (18.4%) or 30-50% (16.5%) versus those who had a minimal change (13.9%, p < 0.01 and p = 0.046). When the relative MAP increased greater than 50%, the rate of neurologic complications was 16.9% versus 13.1% those with minimal change ( p = 0.007). In a multivariable model adjusting for confounders, a relative decrease in Pa co2 greater than 30% was independently associated with greater odds of neurologic complication (odds ratio [OR], 1.25; 95% CI, 1.07-1.46; p = 0.005). Within this group, with a relative decrease in Pa co2 greater than 30%, the effects of increased relative MAP increased neurologic complications (0.05% per BP Percentile; 95% CI, 0.001-0.11; p = 0.05). CONCLUSIONS: In pediatric patients, a large decrease in Pa co2 and increase in MAP following ECMO initiation are both associated with neurologic complications. Future research focusing on managing these issues carefully soon after ECMO deployment can potentially help to reduce neurologic complications.

Validation of extracorporeal membrane oxygenation mortality prediction and severity of illness scores in an international COVID-19 cohort.

BACKGROUND: Veno-venous extracorporeal membrane oxygenation (V-V ECMO) is a lifesaving support modality for severe respiratory failure, but its resource-intensive nature led to significant controversy surrounding its use during the COVID-19 pandemic. We report the performance of several ECMO mortality prediction and severity of illness scores at discriminating survival in a large COVID-19 V-V ECMO cohort. METHODS: We validated ECMOnet, PRESET (PREdiction of Survival on ECMO Therapy-Score), Roch, SOFA (Sequential Organ Failure Assessment), APACHE II (acute physiology and chronic health evaluation), 4C (Coronavirus Clinical Characterisation Consortium), and CURB-65 (Confusion, Urea nitrogen, Respiratory Rate, Blood Pressure, age >65 years) scores on the ISARIC (International Severe Acute Respiratory and emerging Infection Consortium) database. We report discrimination via Area Under the Receiver Operative Curve (AUROC) and Area under the Precision Recall Curve (AURPC) and calibration via Brier score. RESULTS: We included 1147 patients and scores were calculated on patients with sufficient variables. ECMO mortality scores had AUROC (0.58-0.62), AUPRC (0.62-0.74), and Brier score (0.286-0.303). Roch score had the highest accuracy (AUROC 0.62), precision (AUPRC 0.74) yet worst calibration (Brier score of 0.3) despite being calculated on the fewest patients (144). Severity of illness scores had AUROC (0.52-0.57), AURPC (0.59-0.64), and Brier Score (0.265-0.471). APACHE II had the highest accuracy (AUROC 0.58), precision (AUPRC 0.64), and best calibration (Brier score 0.26). CONCLUSION: Within a large international multicenter COVID-19 cohort, the evaluated ECMO mortality prediction and severity of illness scores demonstrated inconsistent discrimination and calibration highlighting the need for better clinically applicable decision support tools.

Association Between the Use of a Digital Health Platform During Pregnancy and Helping Users Avoid Emergency and In-Person Care: Retrospective Observational Study.

BACKGROUND: Almost one-third of pregnant people visit the emergency room during pregnancy. Although some emergency care is necessary, gaps in patient education and inaccessibility of preventive services have been identified as key reasons for high-cost, low-value care in pregnancy. Digital platforms present a promising solution for providing resources to supplement routine prenatal care, thereby reducing the use of low-value in-person services. OBJECTIVE: This study aimed to describe the relationship between the use of Maven and in-person care avoidance (emergency room or office visits) during pregnancy. Maven is a digital prenatal health platform that supplements routine prenatal care. Maven offers educational content (articles, videos, and classes), care coordination (through a care advocate), and provider services (web-based appointments and communication with providers) designed to complement prenatal care. Specifically, the aims of this study were to examine whether the use of Maven is associated with in-person care avoidance overall and whether improvements in pregnancy-related knowledge facilitate in-person care avoidance. To assess aim 2, we tested if the use of Maven is associated with improvements in self-reported understanding of warning signs and medically accurate information and if self-reported understanding of medically accurate information and warning signs is associated with in-person care avoidance in a population of Maven users. METHODS: In this retrospective study, we used adjusted logistic regression to examine the relationship between digital platform use, avoidance of in-person care, and the platform's influence on pregnancy-related knowledge (learning medically accurate information and recognizing warning signs). Demographics, medical history, and in-person care avoidance were self-reported. RESULTS: Of the 5263 users, 280 (5.32%) reported that Maven helped them avoid in-person care during pregnancy. More users who reported avoiding in-person care also reported that the digital platform helped them understand warning signs (231/280, 82.5%) and learned medically accurate information (185/280, 66.1%). In the adjusted models, all modes of digital service use (assessed as quartiles) were associated with avoiding in-person care in a dose-response manner (eg, web-based provider appointments: Q2 adjusted odds ratio [aOR] 1.57, 95% CI 1.00-2.41; Q3 aOR 2.53, 95% CI 1.72-3.72; Q4 aOR 5.26, 95% CI 3.76-7.42). Users were more likely to avoid in-person care if they reported that Maven helped them recognize warning signs (aOR 3.55, 95% CI 2.60-4.94) or learn medically accurate information (aOR 2.05, 95% CI 1.59-2.67). CONCLUSIONS: These results suggest that digital platforms can be effective in helping patients to avoid in-person care. The educational pathway suggests that digital platforms can be particularly effective in helping patients recognize warning signs and learn medically accurate information, which may help them avoid in-person care by recognizing when in-person care is medically appropriate. Future work is needed to assess other pathways through which digital resources can support pregnant people and improve perinatal care use.

Engineered Chimeras Unveil Swappable Modular Features of Fatty Acid and Polyketide Synthase Acyl Carrier Proteins.

The strategic redesign of microbial biosynthetic pathways is a compelling route to access molecules of diverse structure and function in a potentially environmentally sustainable fashion. The promise of this approach hinges on an improved understanding of acyl carrier proteins (ACPs), which serve as central hubs in biosynthetic pathways. These small, flexible proteins mediate the transport of molecular building blocks and intermediates to enzymatic partners that extend and tailor the growing natural products. Past combinatorial biosynthesis efforts have failed due to incompatible ACP-enzyme pairings. Herein, we report the design of chimeric ACPs with features of the actinorhodin polyketide synthase ACP (ACT) and of the Escherichia coli fatty acid synthase (FAS) ACP (AcpP). We evaluate the ability of the chimeric ACPs to interact with the E. coli FAS ketosynthase FabF, which represents an interaction essential to building the carbon backbone of the synthase molecular output. Given that AcpP interacts with FabF but ACT does not, we sought to exchange modular features of ACT with AcpP to confer functionality with FabF. The interactions of chimeric ACPs with FabF were interrogated using sedimentation velocity experiments, surface plasmon resonance analyses, mechanism-based cross-linking assays, and molecular dynamics simulations. Results suggest that the residues guiding AcpP-FabF compatibility and ACT-FabF incompatibility may reside in the loop I, α-helix II region. These findings can inform the development of strategic secondary element swaps that expand the enzyme compatibility of ACPs across systems and therefore represent a critical step toward the strategic engineering of "un-natural" natural products.

Variation in guideline-based prenatal care in a commercially insured population.

BACKGROUND: Despite the importance of prenatal care, quality measurement efforts have focused on the number of prenatal visits, or prenatal care adequacy, rather than the services received. It is unknown whether attending more prenatal visits is associated with receiving more guideline-based prenatal care services. The relationship between guideline-based prenatal care and patients' clinical and sociodemographic characteristics has also not been studied. OBJECTIVE: This study aimed to measure the receipt of guideline-based prenatal care among pregnant patients and to describe the association between guideline-based prenatal care and the number of prenatal visits and other patient characteristics. STUDY DESIGN: This was a retrospective descriptive cohort study of 176,092 pregnancy episodes between 2016 and 2019. We used de-identified administrative claims data on commercial enrollees across the United States from the OptumLabs Data Warehouse. We identified the following 8 components of prenatal care that are universally recommended by the American College of Obstetricians and Gynecologists and other guideline-issuing organizations: testing for sexually transmitted infections, obstetric laboratory test panel, urine culture, urinalysis, anatomy scan ultrasound, oral glucose tolerance test, tetanus, diphtheria, and pertussis vaccine, and group B Streptococcus test. We measured the proportion of pregnant patients who received each of these guideline-based services at the appropriate gestational age. We measured the association between guideline-based services and the number of prenatal visits and prenatal care adequacy. We described variation of guideline-based care according to patient age, comorbidities, high deductible health plan enrollment, and their county's rurality, health professional shortage area status, racial composition, median income, and educational attainment. RESULTS: The 176,092 pregnancy episodes were mostly among patients aged 25 to 34 years (63%) with few pregnancy comorbidities (81%) and living in urban areas (92%). Guideline-based care varied by service, from 51% receiving a timely urinalysis to 90% receiving an anatomy scan and 91% completing testing for sexually transmitted infections. Patients with at least 4 prenatal visits received, on average, 6 of the 8 guideline-based services. Guideline-based care did not increase with additional prenatal visits and varied by patient characteristics. Rates of tetanus, diphtheria, and pertussis vaccination were lower in counties with high proportions of minoritized populations, lower education, and lower income. CONCLUSION: In this commercially insured population, receipt of guideline-based care was not universal, did not increase with the number of prenatal visits, and varied by patient- and area-level characteristics. Measuring guideline-based care is feasible and may capture quality of prenatal care better than visit count or adequacy alone.