Adverse event comparison between glucagon-like peptide-1 receptor agonists and other antiobesity medications following bariatric surgery.

AIM: To compare the incidence of adverse events (AEs) related to antiobesity medications (AOMs; glucagon-like peptide-1 receptor agonists [GLP-1RAs] vs. non-GLP-1RAs) after bariatric surgery. METHODS: This single-centre retrospective cohort included patients (aged 16-65 years) who had undergone laparoscopic Roux-en-Y gastric bypass or sleeve gastrectomy (cohort entry date) and initiated AOMs. Participants were categorized as users of US Food and Drug Administration (FDA)-approved, off-label, or GLP-1RA AOMs if documented as receiving the medication on or after cohort entry date. Non-GLP-1RA AOMs were phentermine, orlistat, topiramate, canagliflozin, dapagliflozin, empagliflozin, naltrexone, bupropion/naltrexone and phentermine/topiramate. GLP-1RA AOMs included: semaglutide, dulaglutide, exenatide and liraglutide. The primary outcome was AE incidence. Logistic regression was used to determine the association of AOM exposure with AEs. RESULTS: We identified 599 patients meeting our inclusion criteria, 83% of whom were female. Their median (interquartile range [IQR]) age was 47.8 (40.9-55.4) years. The median duration of surgery to AOM exposure was 30 months. GLP-1RAs use was not associated with higher odds of AEs: adjusted odds ratio (aOR) 1.1 (95% confidence interval [CI] 0.5-2.6) and aOR 1.1 (95% CI 0.6-2.3) for GLP-1RA versus FDA-approved and off-label AOM use, respectively. AOM initiation ≥12 months after surgery was associated with lower risk of AEs compared to <12 months (aOR 0.01 [95% CI 0.0-0.01]; p < 0.001). CONCLUSION: Our results showed that GLP-1RA AOMs were not associated with an increased risk of AEs compared to non-GLP-1RA AOMs in patients who had previously undergone bariatric surgery. Prospective studies are needed to identify the optimal timeframe for GLP-1RA initiation.

The TOTAL trial for weight management participation: A randomized controlled trial protocol.

BACKGROUND: The three types of evidence-based treatment options for adults with overweight and obesity - behavioral weight management, anti-obesity medications (AOM), and bariatric surgery - are underutilized in the Veterans Health Administration (VHA) system. Our objective in this manuscript is to describe the study protocol for an adequately powered randomized controlled trial (RCT) of a behavioral intervention: TOTAL (Teaching Obesity Treatment Options to Adult Learners) to increase patient uptake of obesity treatment. METHODS: In this multi-site, parallel, RCT, eligible Veterans with a body mass index [BMI] ≥ 27 who had not received obesity treatment within the past 12 months were randomly assigned to TOTAL or usual care. TOTAL involves watching an 18-min video that highlights obesity health risks, pros/cons of all three evidence-based obesity treatments, and expected treatment outcomes. It also includes motivational sessions delivered via televideo at 2 weeks, 6 months, and 12 months after the video (target n = 494 participants). The primary outcome is initiation of behavioral weight management treatment within 18 months of randomization. Secondary outcomes include sustained behavioral weight management treatment, initiation of AOM, bariatric surgery referral, and weight change across 18 months. CONCLUSION: TOTAL, which seeks to increase delivery of weight management treatment within the largest integrated health system in the U.S., combines patient education with motivational interviewing components. If efficacious in this trial, further evaluation of intervention effectiveness and implementation throughout the VHA and other healthcare systems would be warranted.

Electron Capture vs Transfer Dissociation for Site Determination of Tryptic Peptide Tyrosine Sulfation: Direct Detection of Fibrinogen Sulfation Sites and Identification of Novel Isobaric Interferences.

Tyrosine sulfation, an understudied but crucial post-translational modification, cannot be directly detected in conventional nanoflow liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) due to the extreme sulfate lability. Here, we report the detection of sulfate-retaining fragments from LC-electron capture dissociation (ECD) and nanoLC-electron transfer higher energy collision dissociation (EThcD). Sulfopeptide candidates were identified by Proteome Discoverer and MSFragger analysis of nanoLC-HCD MS/MS data and added to inclusion lists for LC-ECD or nanoLC-EThcD MS/MS. When this approach failed, targeted LC-ECD with fixed m/z isolation windows was performed. For the plasma protein fibrinogen, the known pyroglutamylated sulfopeptide QFPTDYDEGQDDRPK from the beta chain N-terminus was identified despite a complete lack of sulfate-containing fragment ions. The peptide QVGVEHHVEIEYD from the gamma-B chain C-terminus was also identified as sulfated or phosphorylated. This sulfopeptide is not annotated in Uniprot but was previously reported. MSFragger further identified a cysteine-containing peptide from the middle of the gamma chain as sulfated and deamidated. NanoLC-EThcD and LC-ECD MS/MS confirmed the two former sulfopeptides via sulfate-retaining fragment ions, whereas an unexpected fragmentation pattern was observed for the third sulfopeptide candidate. Manual interpretation of the LC-ECD spectrum revealed two additional isobaric identifications: a trisulfide-linked cysteinyl-glycine or a carbamidomethyl-dithiothreiotol covalent adduct. Synthesis of such adducts confirmed the latter identity.

Selective Gold Precipitation by a Tertiary Diamide Driven by Thermodynamic Control.

The simple diamide ligand L was previously shown to selectively precipitate gold from acidic solutions typical of e-waste leach streams, with precipitation of gallium, iron, tin, and platinum possible under more forcing conditions. Herein, we report direct competition experiments to afford the order of selectivity. Thermal analysis indicates that the gold-, gallium-, and iron-containing precipitates present as the most thermodynamically stable structures at room temperature, while the tin-containing structure does not. Computational modeling established that the precipitation process is thermodynamically driven, with ion exchange calculations matching the observed experimental selectivity ordering. Calculations also show that the stretched ligand conformation seen in the X-ray crystal structure of the gold-containing precipitate is more strained than in the structures of the other metal precipitates, indicating that intermolecular interactions likely dictate the selectivity ordering. This was confirmed through a combination of Hirshfeld, noncovalent interaction (NCI), and quantum theory of atoms in molecules (QTAIM) analyses, which highlight favorable halogen···halogen contacts between metalates and pseudo-anagostic C-H···metal interactions in the crystal structure of the gold-containing precipitate.

A Novel Model for Xenograft Right Ventricle to Pulmonary Artery Conduit.

The last 40 years have shown dramatic improvement in outcomes for neonatal cardiac surgery for a spectrum of congenital heart disease diagnoses. With more patients surviving into adulthood, the long-term impact of initial management strategies of these patients has come into focus. This is particularly true for patients with pediatric heart valve disease. Many patients born with right ventricular to pulmonary artery (RVPA) discontinuity require placement of a valved conduit in the neonatal period. Valved conduit options are limited in this patient population due to patient size and inability to respond to somatic growth. Genetically engineered porcine (GEP) donors may offer a xenograft conduit alternative that can grow with the patient. We have developed a model utilizing GEP donor RVPA conduits placed in infantile nonhuman primate (NHP) recipients. Our recipient is maintained on single-drug immunosuppression and demonstrates no evidence of pulmonary valve insufficiency or stenosis during short-term follow-up. Further studies and long-term outcomes are necessary to determine the utility of this technology in human application.

Standardized indolent systemic mastocytosis evaluations across a healthcare system: implications for screening accuracy.

Timely diagnosis of systemic mastocytosis (SM) remains challenging due to care heterogeneity. We implemented a standardized approach for SM screening and diagnosis utilizing a novel healthcare system-wide international screening registry. A retrospective analysis assessed rates of SM, cutaneous mastocytosis (CM), and molecular diagnoses before and two years after care standardization. Accuracy of individual and combined SM screening tests - basal serum tryptase (BST) ≥11.5 and ≥20.0 ng/mL, REMA ≥2, monomorphic maculopapular CM, and elevated BST based upon tryptase genotype - was analyzed. Tryptase genotyping and high-sensitivity KIT p.D816V testing increased substantially two years following care standardization. SM diagnoses doubled from 47 to 94 and KIT p.D816V molecular diagnoses increased from 24 to 79. Mean BST and KIT p.D816V variant allele frequency (VAF) values were significantly lower in patients diagnosed after standardization. Hereditary-alpha tryptasemia prevalence was increased in SM prior to care standardization at 4/30 (13.3%) but reflected the general population prevalence two years later at 5/76 (6.6%). Elevated BST based upon genotype and BST ≥11.5 ng/mL had the highest sensitivities at 84.2% and 88.3%, respectively. Presence of monomorphic MPCM, elevated BST based upon tryptase genotype, and the combination of REMA ≥2 with elevated BST based upon tryptase genotype had specificities >90%. BST >20.0 ng/mL had low sensitivity and specificity and was not required to establish any indolent SM diagnosis. Care standardization increased SM diagnosis rates, particularly in patients with low BSTs. Stratifying BST based upon genotype had the best overall sensitivity and specificity of any indolent SM screening test and improved the REMA score specificity.

Exploring Social Support Dynamics After Bariatric Surgery: Insights From Patients and Providers.

INTRODUCTION: Weight loss after bariatric surgery is impacted by several factors, and social support is one of them. Our objective was to characterize patient and provider perceptions about social support after bariatric surgery. METHODS: We reported a secondary analysis of qualitative data acquired from semi-structured interviews conducted from January-November 2020 with bariatric surgery patients and providers. Participants included primary care providers, health psychologists, registered dietitians, bariatric surgeons, and patients with at least 1 y of follow-up after their bariatric procedure. Interview guides were designed using a hybrid of Andersen's Behavioral Model of Health Services and Torain's Framework for Surgical Disparities. Using directed content analysis, study team members generated codes, which were categorized into themes about social support pertaining to dietary habits, physical activity, and follow-up care. RESULTS: Forty-five participants were interviewed, including 24 patients (83% female; 79% White; mean age 50.6 ± 10.7 y) and 21 providers (six primary care providers, four health psychologists, five registered dieticians, and six bariatric surgeons). We identified four themes relating to social support affecting weight loss after surgery: (1) family involvement in helping patients adjust to the bariatric diet, (2) engagement in activities with partners/friends, (3) help with transportation to appointments, and (4) life stressors experienced by patients within their social relationships. CONCLUSIONS: Continued assessment of interpersonal factors after bariatric surgery is essential for weight loss maintenance. Providers can contribute by reinforcing the facilitators of social support and making referrals that may help patients overcome barriers to social support for sustained weight loss after surgery.

Long-Term Cochlear Implant Sound Processor Usage in Children with Single-Sided Deafness.

OBJECTIVE: To assess cochlear implant (CI) sound processor usage over time in children with single-sided deafness (SSD) and identify factors influencing device use. STUDY DESIGN: Retrospective, chart review study. SETTING: Pediatric tertiary referral center. PATIENTS: Children with SSD who received CI between 2014 and 2020. OUTCOME MEASURE: Primary outcome was average daily CI sound processor usage over follow-up. RESULTS: Fifteen children with SSD who underwent CI surgery were categorized based on age of diagnosis and surgery timing. Over an average of 4.3-year follow-up, patients averaged 4.6 hours/day of CI usage. Declining usage trends were noted over time, with the first 2 years postactivation showing higher rates. No significant usage differences emerged based on age, surgery timing, or hearing loss etiology. CONCLUSIONS: Long-term usage decline necessitates further research into barriers and enablers for continued CI use in pediatric SSD cases.

Loci on chromosome 20 interact with rs16969968 to influence cigarettes per day in European ancestry individuals.

BACKGROUND: The understanding of the molecular genetic contributions to smoking is largely limited to the additive effects of individual single nucleotide polymorphisms (SNPs), but the underlying genetic risk is likely to also include dominance, epistatic, and gene-environment interactions. METHODS: To begin to address this complexity, we attempted to identify genetic interactions between rs16969968, the most replicated SNP associated with smoking quantity, and all SNPs and genes across the genome. RESULTS: Using the UK Biobank European subsample, we found one SNP, rs1892967, and two genes, PCNA and TMEM230, that showed a significant genome-wide interaction with rs16969968 for log10 CPD and raw CPD, respectively, in a sample of 116 442 individuals who self-reported currently or previously smoking. We extended these analyses to individuals of South Asian descent and meta-analyzed the combined sample of 117 212 individuals of European and South Asian ancestry. We replicated the gene findings in a meta-analysis of five Finnish samples (N=40 140): FinHealth, FINRISK, Finnish Twin Cohort, GeneRISK, and Health-2000-2011. CONCLUSIONS: To our knowledge, this represents the first reliable epistatic association between single nucleotide polymorphisms for smoking behaviors and provides a novel direction for possible future functional studies related to this interaction. Furthermore, this work demonstrates the feasibility of these analyses by pooling multiple datasets across various ancestries, which may be applied to other top SNPs for smoking and/or other phenotypes.

Observations on the transmission of Dientamoeba fragilis and the cyst life cycle stage.

Little is known about the life cycle and mode of transmission of Dientamoeba fragilis. Recently it was suggested that fecal­oral transmission of cysts may play a role in the transmission of D. fragilis. In order to establish an infection, D. fragilis is required to remain viable when exposed to the pH of the stomach. In this study, we investigated the ability of cultured trophozoites to withstand the extremes of pH. We provide evidence that trophozoites of D. fragilis are vulnerable to highly acidic conditions. We also investigated further the ultrastructure of D. fragilis cysts obtained from mice and rats by transmission electron microscopy. These studies of cysts showed a clear cyst wall surrounding an encysted parasite. The cyst wall was double layered with an outer fibrillar layer and an inner layer enclosing the parasite. Hydrogenosomes, endoplasmic reticulum and nuclei were present in the cysts. Pelta-axostyle structures, costa and axonemes were identifiable and internal flagellar axonemes were present. This study therefore provides additional novel details and knowledge of the ultrastructure of the cyst stage of D. fragilis.

α-Carboxysome Size Is Controlled by the Disordered Scaffold Protein CsoS2.

Carboxysomes are protein microcompartments that function in the bacterial CO2 concentrating mechanism (CCM) to facilitate CO2 assimilation. To do so, carboxysomes assemble from thousands of constituent proteins into an icosahedral shell, which encapsulates the enzymes Rubisco and carbonic anhydrase to form structures typically > 100 nm and > 300 megadaltons. Although many of the protein interactions driving the assembly process have been determined, it remains unknown how size and composition are precisely controlled. Here, we show that the size of α-carboxysomes is controlled by the disordered scaffolding protein CsoS2. CsoS2 contains two classes of related peptide repeats that bind to the shell in a distinct fashion, and our data indicate that size is controlled by the relative number of these interactions. We propose an energetic and structural model wherein the two repeat classes bind at the junction of shell hexamers but differ in their preferences for the shell contact angles, and thus the local curvature. In total, this model suggests that a set of specific and repeated interactions between CsoS2 and shell proteins collectively achieve the large size and monodispersity of α-carboxysomes.

Racial disparities in selected micronutrient deficiencies after bariatric surgery: A systematic review.

BACKGROUND: Bariatric surgery has been associated with numerous micronutrient deficiencies. Several observational studies have found that these deficiencies are more common in racially/ethnically minoritized patients. OBJECTIVES: To conduct a systematic review to investigate whether racially/ethnically minoritized patients experience worse nutritional outcomes after bariatric surgery. SETTING: University of Wisconsin-Madison. METHODS: PubMed, CINAHL, PsychINFO, and Cochrane databases were queried. We searched for manuscripts that reported micronutrient levels or conditions related to micronutrient deficiencies according to race/ethnicity (White, African American/Black, and Hispanic) after laparoscopic sleeve gastrectomy or Roux-en-Y gastric bypass between 2002 and 2022. Eleven micronutrients (vitamins A, B1 [thiamine], B12, D, E, K, calcium, copper, folate, iron, and zinc), and four conditions (anemia, bone loss, fractures, and hyperparathyroidism) were assessed. RESULTS: Abstracts from 953 manuscripts were screened; 18 full-text manuscripts were reviewed for eligibility, and ten met the inclusion criteria. Compared to White patients, African Americans had a higher prevalence of thiamine, vitamin D, and vitamin A deficiencies. There were no differences in calcium and vitamin B12 deficiencies. The other six micronutrients were not assessed according to race/ethnicity. Hyperparathyroidism was more prevalent in African Americans than White patients in the three studies that evaluated it. The prevalence of fractures was mixed. Anemia and bone loss were not evaluated according to race/ethnicity. CONCLUSIONS: Although the literature on micronutrient outcomes following bariatric surgery according to race/ethnicity is limited, African Americans appear to experience a higher prevalence of vitamin deficiencies and associated conditions. Qualitative and quantitative research to explore these disparities is warranted.

MerTK is a mediator of alpha-synuclein fibril uptake by human microglia.

Mer tyrosine kinase (MerTK) is a receptor tyrosine kinase that mediates non-inflammatory, homeostatic phagocytosis of diverse types of cellular debris. Highly expressed on the surface of microglial cells, MerTK is of importance in brain development, homeostasis, plasticity and disease. Yet, involvement of this receptor in the clearance of protein aggregates that accumulate with ageing and in neurodegenerative diseases has yet to be defined. The current study explored the function of MerTK in the microglial uptake of alpha-synuclein fibrils which play a causative role in the pathobiology of synucleinopathies. Using human primary and induced pluripotent stem cell-derived microglia, the MerTK-dependence of alpha-synuclein fibril internalization was investigated in vitro. Relevance of this pathway in synucleinopathies was assessed through burden analysis of MERTK variants and analysis of MerTK expression in patient-derived cells and tissues. Pharmacological inhibition of MerTK and siRNA-mediated MERTK knockdown both caused a decreased rate of alpha-synuclein fibril internalization by human microglia. Consistent with the non-inflammatory nature of MerTK-mediated phagocytosis, alpha-synuclein fibril internalization was not observed to induce secretion of pro-inflammatory cytokines such as IL-6 or TNF, and downmodulated IL-1ß secretion from microglia. Burden analysis in two independent patient cohorts revealed a significant association between rare functionally deleterious MERTK variants and Parkinson's disease in one of the cohorts (P = 0.002). Despite a small upregulation in MERTK mRNA expression in nigral microglia from Parkinson's disease/Lewy body dementia patients compared to those from non-neurological control donors in a single-nuclei RNA-sequencing dataset (P = 5.08 × 10-21), no significant upregulation in MerTK protein expression was observed in human cortex and substantia nigra lysates from Lewy body dementia patients compared to controls. Taken together, our findings define a novel role for MerTK in mediating the uptake of alpha-synuclein fibrils by human microglia, with possible involvement in limiting alpha-synuclein spread in synucleinopathies such as Parkinson's disease. Upregulation of this pathway in synucleinopathies could have therapeutic values in enhancing alpha-synuclein fibril clearance in the brain.

ATM inhibition augments type I interferon response and antitumor T-cell immunity when combined with radiation therapy in murine tumor models.

BACKGROUND: Radiation therapy (RT) elicits DNA double-strand breaks, resulting in tumor cytotoxicity and a type I interferon (IFN) response via stimulator of interferon genes (STING) activation. We investigated whether combining RT with an ataxia-telangiectasia mutated inhibitor promoted these effects and amplified tumor immunity. METHODS: Mice-bearing syngeneic flank tumors (MOC2 head and neck squamous cell carcinoma or B78 melanoma) were treated with tumor-directed RT and oral administration of AZD0156. Specific immune cell depletion, type 1 interferon receptor 1 knock-out mice (IFNAR1-KO), and STING-deficient tumor cells were used to investigate tumor-immune crosstalk following RT and AZD0156 treatment. RESULTS: Combining RT and AZD0156 reduced tumor growth compared with RT or AZD0156 alone in mice bearing MOC2 or B78 tumors. Low-dose AZD0156 (1-100 nM) alone did not affect tumor cell proliferation but suppressed tumor cell clonogenicity in combination with RT. Low-dose AZD0156 with RT synergistically increased IFN-ß, major histocompatibility complex (MHC)-I, and programmed death-ligand 1 (PD-L1) expression in tumor cells. In contrast to wild-type mice, IFNAR1-KO mice showed reduced CD8+T cell tumor infiltration and poor survival following RT+AZD0156 treatment. CD8+T cell depletion reduced antitumor response during RT+AZD0156 treatment. STING-deficient MOC2 (MOC2-STING+/-) or B78 (B78-STING-/-) tumors eliminated the effects of RT+AZD0156 on the expression of IFN-ß, MHC-I, and PD-L1, and reduced CD8+T cell infiltration and migration. Additional anti-PD-L1 therapy promoted antitumor response by elevation of tumor-MHC-I and lymphocyte activation. CONCLUSIONS: Combined radiation and AZD0156 increase STING-dependent antitumor response. Tumor-derived cell-autonomous IFN-ß amplification drives both MHC-I and PD-L1 induction at the tumor cell surface, which is required by anti-PD-L1 therapy to promote antitumor immune response following RT and AZD0156 combination therapy.

Lung tumor-infiltrating Treg have divergent transcriptional profiles and function linked to checkpoint blockade response.

Regulatory T cells (Treg) are conventionally viewed as suppressors of endogenous and therapy-induced antitumor immunity; however, their role in modulating responses to immune checkpoint blockade (ICB) is unclear. In this study, we integrated single-cell RNA-seq/T cell receptor sequencing (TCRseq) of >73,000 tumor-infiltrating Treg (TIL-Treg) from anti-PD-1-treated and treatment-naive non-small cell lung cancers (NSCLC) with single-cell analysis of tumor-associated antigen (TAA)-specific Treg derived from a murine tumor model. We identified 10 subsets of human TIL-Treg, most of which have high concordance with murine TIL-Treg subsets. Only one subset selectively expresses high levels of TNFRSF4 (OX40) and TNFRSF18 (GITR), whose engangement by cognate ligand mediated proliferative programs and NF-κB activation, as well as multiple genes involved in Treg suppression, including LAG3. Functionally, the OX40hiGITRhi subset is the most highly suppressive ex vivo, and its higher representation among total TIL-Treg correlated with resistance to PD-1 blockade. Unexpectedly, in the murine tumor model, we found that virtually all TIL-Treg-expressing T cell receptors that are specific for TAA fully develop a distinct TH1-like signature over a 2-week period after entry into the tumor, down-regulating FoxP3 and up-regulating expression of TBX21 (Tbet), IFNG, and certain proinflammatory granzymes. Transfer learning of a gene score from the murine TAA-specific TH1-like Treg subset to the human single-cell dataset revealed a highly analogous subcluster that was enriched in anti-PD-1-responding tumors. These findings demonstrate that TIL-Treg partition into multiple distinct transcriptionally defined subsets with potentially opposing effects on ICB-induced antitumor immunity and suggest that TAA-specific TIL-Treg may positively contribute to antitumor responses.

Perceptions of Facilitators and Barriers to Smoking Cessation Among Patients and Providers in a Cancer Center: A Single Institution Qualitative Exploratory Study.

PURPOSE: Cancer patients who remain tobacco users have poorer outcomes, including increased mortality and decreased treatment tolerance; however, cessation post-diagnosis is challenging. Our formative research explored cessation-related perspectives among patients and staff at one National Cancer Institute-designated cancer center, to inform improving cessation services within oncology care. METHODS: Using a descriptive phenomenological approach, a purposive sample of current cancer patients (n = 13) and cancer center physicians and cessation program staff (n = 9) were recruited to complete one-on-one audio-recorded in-depth qualitative interviews, to explore experiences providing or receiving cessation support, and perspectives on patients' readiness and needs regarding cessation. Thematic coding utilized Green's predisposing, enabling, and reinforcing framework to identify factors having positive, negative, or mixed impact on delivery of best-practices cessation services (ie, 5As) and patient cessation success. RESULTS: Patients identified cancer diagnosis as a wake-up call, existing health problems, persistent healthcare providers, cost of cigarettes, and societal disapproval of smoking as factors facilitating quitting. Futility of quitting after a cancer diagnosis, cost and logistics of program participation, clinician time constraints, and lifetime addiction made quitting harder. Family, friends, stigma and motivation, and pharmacotherapies played mixed roles. Patients felt survivor-focused cessation programs, including stress management, could better enable quitting. Provider-anticipated problems with implementing cessation counseling included so-called "therapeutic nihilism" (ie, pessimism regarding cessation post-diagnosis), lack of training and standardized approaches, and time and documentation burden. Clinicians saw both policies and peer clinician "champions" as potentially increasing prioritization of cessation within oncology. CONCLUSIONS: Findings highlight unmet needs for patients and providers regarding provision of effective cessation care. Despite survival benefit, cessation is still not standard within cancer care. Our results show that many patients would benefit from standardized programs where they are routinely asked about cessation. Providers would benefit from both structural enhancements and professional education to ensure that evidence-based cessation services tailored to cancer patients, are offered throughout treatment and survivorship.

Optimization of the Electronic Health Record for Research.

Mini Abstract This surgical perspective highlights the current limitations of utilizing the electronic health record for research and discusses directions for future optimization.