Faculty Bibliography

SARS-CoV-2 infection is associated with platelet hyperreactivity and increased rates of arterial and venous thrombosis. SARS-CoV-2 mutations have resulted in several variants with differences in transmissibility, infectivity, and patient outcomes. This study investigates the effects of the ancestral strain of SARS-CoV-2 (WA1) and two variants of concern, Delta and Omicron, on the human megakaryocyte (MK) phenotype and transcriptome. Human CD34⁺-derived MKs were incubated with WA1, Delta or Omicron SARS-CoV-2 variants for 24 hours. MK activation markers were measured under resting and thrombin-stimulated conditions. RNA-seq and cytokine release in response to the viruses were assessed. Plasma cytokines were measured in hospitalized COVID-19 patients. Treatment of MKs with WA1, Delta or Omicron variants of SARS-CoV-2 resulted in similar increases in classical activation markers. However, SARS-CoV-2 variants mediated distinct transcriptomic changes. Across variants, 60 genes overlapped, including CXCL8. Consistent with transcriptomic changes, SARS-CoV-2-incubated MKs secreted significantly elevated levels of IL-8. Among hospitalized COVID-19 patients, plasma IL-8 levels were highest in COVID-19 patients who subsequently experienced thrombotic events or died. In conclusion, WA1, Delta, and Omicron similarly induce classical MK activation responses while mediating distinct transcriptomic changes. Increased IL-8 levels may serve as a biomarker to inform platelet hyperreactivity and thrombotic events associated with COVID-19.

INTRODUCTION/BACKGROUND:Poor social connection is a risk factor for mortality comparable to smoking or obesity. Expert recommendations encourage clinicians to identify and address isolation, loneliness and absent social support; however, screening and documentation norms remain unstandardised in graduate medical education (GME) social determinants of health (SDOH) curricula. We assessed the knowledge, attitudes, and behaviours (KAB) of internal medicine resident physicians in a large, urban, academic medical centre regarding screening for and documenting social connection. METHODS:Between October 2022 and February 2023, a voluntary, anonymous mixed-methods survey was disseminated to assess resident physicians' KAB about social connection as a SDOH. Quantitative data were analysed descriptively. Qualitative responses underwent content analysis. An electronic medical record (EMR) chart review of resident notes corroborated survey data. RESULTS:Sixty-three residents of an eligible 153 responded to the survey (41% participation). Sixty-five per cent reported never receiving formal GME about social connection as a SDOH. Familiarity with validated screening tools was low. Although 51% of respondents reported often/always documenting patients' social support systems, few chart notes explicitly mentioned social contacts. Respondents agreed that physicians are responsible for assessing and documenting social connection and noted key challenges of time constraints, inadequate screening and documentation norms and EMR navigation difficulty. Targeted didactics, EMR improvements and interdisciplinary learning opportunities were identified as potential solutions. CONCLUSIONS:This study identified notable gaps in resident physician KAB to address social connection as a SDOH. Challenges could be addressed with standardised screening and documentation norms and skill development in patient communication and interdisciplinary teamwork.

People with HIV are at increased risk of cardiovascular events; thus, care delivery strategies that increase access to comprehensive cardiovascular disease (CVD) risk management are a priority. We report the results of a multi-component telemedicine-based strategy to improve blood pressure control among people with HIV-Assess and Adapt to the Impact of COVID-19 on CVD Self-Management and Prevention Care in Adults Living with HIV (AAIM-High). The AAIM High strategy is a virtual adaptation of our previously published EXTRA-CVD strategy and consisted of hypertension education and six components: nurse-led care coordination (delivered by teleconference or telephone), home systolic blood pressure (SBP) monitoring, evidence-based treatment algorithms, electronic health records tools, technology coach, and communication preferences assessment. People with HIV (n = 74) with comorbid hypertension at three academic medical centers were enrolled in a single arm implementation study from January 2021 to December 2022. Over 12 months, the average patient-performed home SBP decreased by 7.7 mmHg (95% CI -11.5, -3.9). The percentage of patients at treatment goal, defined as average SBP <130 mmHg, increased from 46.0% to 72.5% at 12 months. By adapting to the growing use of telemedicine in healthcare delivery, our study effectively improved hypertension control in people with HIV through a virtual, nurse-led intervention.

BACKGROUND/UNASSIGNED:Despite their efficacy, medications for opioid use disorder (MOUD) remain underutilized in patients with infections from intravenous opioid use (I-IOU). This study evaluates the impact of an Expanded MOUD Access Initiative (EMAI) on MOUD uptake and other clinical outcomes in patients hospitalized for I-IOU at an institution without addiction medicine consultation. METHODS/UNASSIGNED:We performed a retrospective pre-post study of hospital admissions for I-IOU before (January 2019-June 2021) and after (January 2022-December 2023) EMAI introduction. Data was collected via chart review. The EMAI eliminated restrictions on methadone use and established a new order set for buprenorphine inductions. The primary outcome was MOUD receipt; secondary outcomes included patient directed discharge (PDD) and 30-day re-hospitalization. RESULTS/UNASSIGNED:There were 129 hospitalizations prior to the intervention (control) and 98 after (EMAI). MOUD receipt was significantly higher in the EMAI group (75.5% vs 31.0%; OR, 6.86 [95% CI, 3.84-12.61]). In patients not receiving MOUD prior to admission (n = 176), new inductions occurred more frequently in the EMAI group (68.0% vs 11.9%; OR, 15.76 [95% CI, 7.50-35.78]). PDD was lower in the EMAI group (23.5% vs 48.8%; OR, 0.32 [95% CI, 0.10-0.57]), as was 30-day re-hospitalization (12.2% vs 22.5%; OR, 0.48 [95% CI, 0.22-0.98]). In a multivariable logistic regression model, the EMAI was the only variable to show a statistically significant association with MOUD receipt (aOR, 6.89 [95% CI, 3.75-13.11]). CONCLUSIONS/UNASSIGNED:The EMAI was associated with increased MOUD uptake, reduced PDD, and fewer 30-day re-hospitalizations despite the lack of addiction medicine consultation.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Vascular dysfunction contributes to Alzheimer disease (AD) and related dementias (ADRDs), but the underlying mechanisms remain unclear. Previous studies link midlife hemostasis and platelet aggregation measures to late-life dementia risk. We aimed to determine whether platelet aggregation in midlife is associated with imaging markers of AD pathology. METHODS:F-flortaucipir) PET uptake in dementia-free, middle-aged adults from the Framingham Heart Study. Co-primary outcomes included amyloid and tau uptake in AD-vulnerable regions. We also examined an MRI-based cortical thickness signature of AD risk as a secondary outcome. We used multivariable regression models adjusted for demographic and clinical factors, considering potential nonlinear associations. RESULTS:< 0.035), consistent with a neurodegenerative pattern. DISCUSSION/CONCLUSIONS:Our findings indicate that platelet aggregation is linked to PET and MRI markers of AD pathology as early as midlife. These findings support further investigation of platelet-mediated mechanisms in AD pathogenesis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with an increased risk of vascular dysfunction and cardiovascular disease. We validate our previously developed Systemic Lupus Erythematosus Activity Platelet-Gene Expression Signature (SLAP-GES) score and investigate its relationship with platelet activity and vascular health. SLAP-GES was associated with the SLE Disease Activity Index (Padj < 0.001) and consistent over time (r = 0.76; P = 9 × 10^-5). Moreover, SLAP-GES was associated increased platelet aggregation in response to submaximal epinephrine (P = 0.084), leukocyte platelet aggregates (P = 0.014), and neutrophil platelet aggregates (P = 0.043). SLAP-GES was also associated with impaired glycocalyx (P = 0.011) and brachial artery flow-mediated dilation (P = 0.045). Altogether, SLAP-GES is associated with SLE disease activity, platelet activity, and impaired vascular health.

Organ shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution^1-3. Despite gene-editing, the immune reactions following xenotransplantation can still cause transplant failure⁴. To understand the immunological response of a pig-to-human kidney xenotransplantation, we conducted large-scale multi-omics profiling of the xenograft and the host's blood over a 61-day procedure in a brain-dead human (decedent) recipient. Blood plasmablasts, natural killer (NK) cells, and dendritic cells increased between postoperative day (POD)10 and 28, concordant with expansion of IgG/IgA B-cell clonotypes, and subsequent biopsy-confirmed antibody-mediated rejection (AbMR) at POD33. Human T-cell frequencies increased from POD21 and peaked between POD33-49 in the blood and xenograft, coinciding with T-cell receptor diversification, expansion of a restricted TRBV2/J1 clonotype and histological evidence of a combined AbMR and cell-mediated rejection at POD49. At POD33, the most abundant human immune population in the graft was CXCL9+ macrophages, aligning with IFN-γ-driven inflammation and a Type I immune response. In addition, we see evidence of interactions between activated pig-resident macrophages and infiltrating human immune cells. Xenograft tissue showed pro-fibrotic tubular and interstitial injury, marked by S100A6⁵, SPP1⁶ (Osteopontin), and COLEC11⁷, at POD21-POD33. Proteomics profiling revealed human and pig complement activation, with decreased human component after AbMR therapy with complement inhibition. Collectively, these data delineate the molecular orchestration of human immune responses to a porcine kidney, revealing potential immunomodulatory targets for improving xenograft survival.

Tumor biologic risk has replaced anatomic disease burden for guiding chemotherapy use in HR-positive, early-stage breast cancer. Recent surgical trials support less frequent axillary lymph node dissection, potentially impacting incidence of N2-3 diagnoses. As the field considers applying genomic risk assessment tools for locally advanced, operable HR-positive breast cancer, we estimated current incidence of these cancers, focusing on HR-positive/HER2-negative disease. Of 486,031 cases recorded with Stage I-III HR-positive/HER2-negative disease in the U.S. National Cancer Institute Surveillance, Epidemiology, and End Results-17 database (2010-2021), 28,585 (5.9%) and 23,307 (4.8%) had N2-3M0(Any T) and T3-4N0-1M0 disease, respectively. Invasive lobular cancer, observed across all disease stages and receptor-based subtypes, was highest in HR-positive/HER2-negative locally advanced disease. Incidence of N2-3M0(Any T) decreased for each subtype. Incidence of T3-4N0-1M0 increased for HR-positive/HER2-negative disease but not for the other subtypes. Defining chemotherapy benefit for patients with locally advanced, operable HR-positive breast cancer remains an important clinical question.

Xenotransplantation of genetically-modified pig kidneys offers a solution to the scarcity of organs for end-stage renal disease patients.¹ We performed a 61-day alpha-Gal knock-out pig kidney and thymic autograft transplant into a nephrectomized brain-dead human using clinically approved immunosuppression, without CD40 blockade or additional genetic modification. Hemodynamic and electrolyte stability and dialysis independence were achieved. Post-operative day (POD) 10 biopsies revealed glomerular IgM and IgA deposition, activation of early complement components and mesangiolysis with stable renal function without proteinuria, a phenotype not seen in allotransplantation. On POD 33, an abrupt increase in serum creatinine was associated with antibody-mediated rejection and increased donor-specific IgG. Plasma exchange, C3/C3b inhibition and rabbit anti-thymocyte globulin (rATG), completely reversed xenograft rejection. Pre-existing donor-reactive T cell clones expanded progressively in the circulation post-transplant, acquired an effector transcriptional profile and were detected in the POD 33 rejecting xenograft prior to rATG treatment. This study provides the first long-term physiologic, immunologic, and infectious disease monitoring of a pig-to-human kidney xenotransplant and indicates that pre-existing xenoreactive T cells and induced antibodies to unknown epitope(s) present a major challenge, despite significant immunosuppression. It also demonstrates that a minimally gene-edited pig kidney can support long-term life-sustaining physiologic functions in a human.