Faculty Bibliography

INTRODUCTION/BACKGROUND:Patients with atherosclerotic cardiovascular disease (ASCVD) and systemic inflammation (SI) or chronic kidney disease (CKD) have poorer outcomes than those without SI or CKD. This study evaluated the impact of both SI and CKD on major adverse cardiovascular events (MACE), healthcare costs, and healthcare resource utilization (HCRU) in patients with ASCVD. METHODS:This retrospective cohort study examined the association between SI and revised MACE, healthcare costs, and HCRU among adult patients with ASCVD from the Komodo Healthcare Map®. CKD stage 3-4 was determined from claims or laboratory data. SI was defined as ≥ 1 high-sensitivity C-reactive protein (hsCRP) value of 2-10 mg/l (without SI, all hsCRP values < 2 mg/l). The primary endpoint, revised MACE, was defined as a composite of nonfatal myocardial infarction, nonfatal stroke, and all-cause mortality. RESULTS:Of 74,884 patients with ASCVD and ≥ 1 eligible hsCRP value, 8.5% had CKD stage 3-4, and 49.2% had SI. Patients with SI had a higher comorbidity index and a greater prevalence of obesity, hypertension, and type 2 diabetes than those without SI. Compared with patients with ASCVD without CKD or SI, SI alone was associated with a 24% higher risk (hazard ratio [HR] 1.24; 95% CI 1.15-1.34), CKD stage 3-4 with a 33% higher risk (HR 1.33; 95% CI 1.16-1.51), and both SI and CKD stage 3-4 with a 62% higher risk (HR 1.62; 95% CI 1.45-1.82) of revised MACE. In patients with ASCVD without CKD, total healthcare costs were $18,002 PPPY with SI vs. $15,070 PPPY without SI. In patients with ASCVD with CKD stage 3-4, costs were $26,089 PPPY with SI vs. $20,753 PPPY without SI. Across groups, SI was associated with higher HCRU. CONCLUSIONS:SI is associated with increased risk of MACE and higher total healthcare costs and HCRU in patients with ASCVD with or without CKD.

OBJECTIVES/OBJECTIVE:To evaluate whether real-time electronic health record (EHR)-based secure messaging between emergency department (ED) clinicians and prior discharge teams influences ED disposition decisions for patients re-presenting within 30 days of hospital discharge. MATERIALS AND METHODS/METHODS:This 18-month pre-post study included 27 592 ED revisit encounters across 3 campuses within one academic healthcare system. Robotic process automation generated a real-time EHR secure message connecting the ED attending with the index hospitalization discharge team during the ED disposition window. The primary outcome was the proportion of encounters resulting in ED disposition changes. Secondary outcomes included length of stay and messaging engagement by service, hospital campus, and time of day. RESULTS:Systemwide, inpatient readmissions rates were unchanged (49.4% vs 48.6%, P = .149), and observation status increased (7.0% vs 8.0%, P < .001). At one campus where messaging was paired with proactive care coordination, inpatient admissions decreased (56.9% vs 54.1%, P = .029) and treat-and-release increased (36.8% vs 39.6%, P = .024). Overall, 61.8% of messages received a response, but engagement did not correlate with disposition changes systemwide. DISCUSSION/CONCLUSIONS:Disposition changes occurred only where messaging was integrated with care coordination workflows with the operational capacity to act, indicating that real-time communication alone is insufficient without supporting infrastructure. CONCLUSION/CONCLUSIONS:Real-time EHR messaging may be most effective when paired with structured care coordination models rather than deployed as a standalone alerting tool.

OBJECTIVE:The objectives of this study were to determine 1) the prevalence of perceived mistreatment, 2) the source of mistreatment, and 3) the location where mistreatment occurred among obstetrics and gynecology residents. METHODS:We conducted a national survey of obstetrics and gynecology residents using an adapted validated questionnaire. RESULTS:Over half of participating obstetrics and gynecology residents reported mistreatment. The most common type of mistreatment reported was verbal or emotional abuse (57%). Patients/patients' families, attendings, nurses, and other residents were all common sources of mistreatment. The most frequent location was labor and delivery. Female, gender-diverse, Black, and lesbian, gay, bisexual, queer+ (LGBQ+) residents experienced mistreatment at higher rates. CONCLUSION/CONCLUSIONS:Obstetrics and gynecology residents report a high prevalence of mistreatment. Interventions to reduce mistreatment, especially on labor and delivery, will prove important to promote the respectful work environment necessary for optimal learning and patient care.

The Ca²⁺ release-activated Ca²⁺ (CRAC) channel mediates store-operated calcium entry (SOCE), a ubiquitous pathway essential for many cell types, including immune cells. Three Orai (Orai1/2/3) proteins constitute the plasma membrane pore-forming units of CRAC channels that are activated by the endoplasmic reticulum (ER) Ca²⁺-sensing STIM1/2 proteins when ER Ca²⁺ stores are depleted. Orai1/2/3 are differentially expressed across primary cells with discernible differences in their structures and biophysical properties. Further, Orai1 has two alternatively translated isoforms: long mammalian-specific Orai1α and the 63-residue shorter Orai1β, which is evolutionarily older and conserved across vertebrates. Whether Orai1α/1β/2/3 produce unique cytosolic Ca²⁺ signatures that bias transcriptional responses through effectors like NFAT is unclear. Here, we used HEK293 cells engineered to express one native Orai isoform and show that all Orai isoforms couple to NFAT1/4 induction. The magnitude of NFAT1/4 induction for each Orai isoform matches that of SOCE, with the following profile: Orai1β>Orai1α>>Orai2>Orai3. Near-native re-expression of either Orai1α or Orai1β in primary murine Orai1 ^-/- CD4⁺ T cells restored SOCE, NFAT activation, cytokine production and promoted near identical transcriptional responses enriched for immune activation pathways. An analysis of genetic and clinical data of human individuals showed that homozygous null mutations selectively abolishing Orai1α are not associated with disease resembling CRAC channelopathy. Primary T cells from individuals homozygous or heterozygous for an Orai1α null mutation showed enhanced, rather than impaired, SOCE and NFAT induction. Our data indicate that NFAT activation and transcriptional outputs are primarily driven by the graded strength of SOCE mediated by each isoform of the Orai quartet.

Pollen-food allergy syndrome is an IgE-mediated allergic condition resulting from cross-reactivity between pollen allergens and homologous proteins present in plant-derived foods. PFAS typically presents with rapid-onset itching, burning, swelling, and erythema of the oral cavity and pharynx, with symptoms usually limited to the oropharyngeal region, although systemic reactions, including respiratory or gastrointestinal symptoms and, rarely, anaphylaxis, may occur. PFAS is strongly associated with the atopic phenotype and frequently coexists with allergic rhinitis, atopic dermatitis, and asthma. Available studies show marked variability in prevalence, from a few percent in general pediatric populations to 50-80% among atopic children, especially those with allergic rhinitis, with regional differences likely reflecting pollen sensitization patterns and dietary habits. The aim of this review was to summarize current knowledge regarding the epidemiology, clinical characteristics, molecular determinants, and food-related aspects of PFAS in children across different regions of the world. PFAS is a common but still insufficiently studied condition in children. Standardized diagnostic criteria and large population-based studies incorporating molecular diagnostic approaches are needed to better define the true burden, risk factors, and clinical spectrum of PFAS in childhood.

Alzheimer's disease (AD) is characterised by the intraneuronal aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles and by the extracellular deposition of β-amyloid (Aβ). Tau pathology restricted to the hippocampal formation is frequently observed in the elderly brain in the absence of any Aβ deposition and considered as "primary age-related tauopathy" (PART). Here, we applied an unbiased proteomic approach to determine how concomitant Aβ pathology modifies the neurofibrillary tangle proteome. Neurofibrillary tangles were isolated by dissecting Tau pSer202/pThr205 "AT8" immunopositive neuronal profiles, combining chromogenic immunohistochemistry with laser capture microdissection, from hippocampal sections of 17 post-mortem brains spanning three groups: PART (n = 5; A0, B1-2, C0 scores), intermediate AD (n = 6; A1-2, B2-3, C1-2 scores) and advanced AD (n = 6; A3, B3, C3 scores). A label-free quantitative liquid chromatography-mass spectrometry based proteomic analysis, using data independent acquisition (DIA) on a Bruker timsTOF, was performed. A conserved core of 63 proteins was identified as enriched in tangles across all groups, mostly associated with "RNA binding" and "regulation of mRNA metabolic process", based on the Gene Ontology database. Group-specific signatures were also observed: 33 proteins were significantly enriched only in tangles collected from PART cases and were predominantly linked to "structural molecule activity", whereas Aβ-positive cases showed specific enrichment of "RNA binding" and "cytoplasmic translation" pathways-with intermediate AD cases displaying a transitional profile. Our findings are consistent with PART having distinct tangle proteomic features; however, the majority of its proteomic signature is in common with tangles within the AD continuum. By addressing how Aβ accumulation alters the tangle proteome, this study provides mechanistic insights into the expansion of Tau pathology, paving the way towards the identification of biomarkers and therapeutic strategies that would allow for stabilisation of Tau pathology in the elderly.

OBJECTIVE:The relationship between physical activity and sleep with inflammatory arthritis (IA) is understudied, and existing research has relied largely on self-report or short-term assessments. The NIH All of Us database provides long-term accelerometry data, enabling more precise estimation of the association between lifestyle behaviors and IA. METHODS:Participants from the All of Us database who shared electronic health record and Fitbit data were included. Daily activity and sleep metrics were compared between individuals with and without IA using multiple linear regression. Cox proportional hazards regression was used to examine the association of activity and sleep patterns with incident IA in a 10-year follow-up period. RESULTS:A total of 23,855 participants were included, 200 of whom had IA. Participants with IA took fewer daily steps (P < 0.001) and had greater sleep variability (P < 0.001) compared to those without IA. 122 individuals had incident IA. Every 1,000 extra daily steps were associated with a 7% lower risk of IA (hazard ratio [HR] 0.93 [95% confidence interval (CI) 0.87-0.99], P = 0.02). Compared to those who walked <5,000 steps daily, those who walked 5,000 to 10,000 steps and 10,000+ steps had a 41% (HR 0.59 [95% CI 0.39-0.91], P = 0.02) and 50% (HR 0.50 [95% CI 0.29-0.86], P = 0.01) reduction in risk of IA. CONCLUSION/CONCLUSIONS:Individuals with IA had reduced step counts and more sleep variability compared to those without IA, highlighting how physical activity and sleep contribute to IA. Additionally, increased daily step count was associated with decreased risk of incident IA, suggesting a possible research intervention for those at high risk of IA.

OBJETIVO/OBJECTIVE:Estimar la prevalencia de consumo actual de cannabis en población mexicana de 12 a 65 años, así como la prevalencia de problemas físicos y emocionales, propios o a terceros. Material y métodos. Análisis de la Encuesta Nacional de Consumo de Drogas, Alcohol y Tabaco (Encodat) 2025. Se estimaron prevalencias de consumo en el último mes, la frecuencia de consumo como indicador de intensidad y problemas asociados. RESULTADOS/RESULTS:La prevalencia de consumo actual fue 1.4% (1.3 millones). Entre consumidores actuales, 49.2% reportó consumo semanal o diario, y 26.6% reportó problemas físicos o emocionales asociados. CONCLUSIONES/CONCLUSIONS:Actualmente, más de 1.3 millones de personas en México, consumen cannabis con alta intensidad y presentan problemas asociados. Pese a la baja prevalencia, es importante establecer vigilancia y prevención enfocados en el consumo frecuente.

Previous epidemiological studies have shown that E-cigarette and tobacco users are more likely to develop COVID-19 symptoms than non-users. To investigate the underlying mechanisms, we examined the effects of nicotine, the major component of tobacco and E-cigarette, and its major metabolite, cotinine, on the susceptibility of human respiratory epithelial cells to SARS-CoV-2 infection. We found that pre-treatment with nicotine and cotinine significantly and additively enhanced viral infection. While nicotine increased the expression of the viral receptor ACE2 and the serine protease TMPRSS2, cotinine upregulated cysteine protease cathepsin B and promoted viral spike protein cleavage. These findings suggest that nicotine and cotinine enhance SARS-CoV-2 infection at the cell entry stage through distinct mechanisms. Using a SARS-CoV-2 pseudovirus system, we further investigated the effects and mechanisms of nicotine and cotinine on viral entry. We found that both compounds enhanced pseudovirus infection, but with different time courses. Nicotine's effect correlated with the upregulation of ACE2 and TMPRSS2, whereas cotinine's effect corresponded with increased cathepsin B and viral spike protein cleavage. The cathepsin B inhibitor E64d completely abolished cotinine-enhanced viral spike protein cleavage and viral entry. In contrast, ACE2 and TMPRSS2 inhibitors (chloromethylketone and camostat) had limited effects on viral spike protein cleavage and only partially reduced the viral entry enhancement induced by nicotine and cotinine. These results indicate that nicotine promotes virus-receptor binding and cell entry, while cotinine facilitates viral entry through cathepsin B-mediated spike protein cleavage.IMPORTANCEThis study highlights the potential risks of tobacco and E-cigarette use in increasing susceptibility to COVID-19. We show that the major neurostimulant in tobacco and E-cigarette, nicotine, and its metabolite, cotinine, additively enhance SARS-CoV-2 infection in human respiratory epithelial cells by promoting viral entry. Specifically, nicotine and cotinine upregulate the expression of distinct, yet complementary sets of key cellular proteins required for viral entry. These findings suggest that both tobacco smoking and E-cigarette vaping may exacerbate COVID-19 infection rates and severity and provide new insights into how nicotine and cotinine contribute to viral susceptibility. This research underscores the need for public health measures to address the heightened risk posed by tobacco smoking and E-cigarette vaping to encounter the SARS-CoV-2 infection.

State sequence analysis of longitudinal categorical data seeks to synthesize pathways through different dimensions of the life course for descriptive, associative and predictive purposes. Given the number and variety of patterns in such data, measures of the dynamic features of sequences are used to characterize them. One, based on the information-theoretic notion of entropy, measures the uncertainty in the state that will be active at a given time. We customize its use to establish the extent to which we are ignorant, or unsure, of what happens next in a dynamic process, conditional on its past. Relying on different Markov chain models for nominal state sequences, we establish multiple measures of uncertainty that allow us to adjust expectations to reflect individual-specific differences and historical information. We establish complementary measures to assess the predictive power of the models in the context of this uncertainty. In so doing, we can summarize and contrast the change in uncertainty associated with different models. As is common in this field, we consider ways in which data can be stratified through demographics and clustering, and how this additional level of partitioning builds a more complete narrative of the social process.