United States

### Background
Despite the success of antiviral treatment for HIV-1 infection, people living with HIV (PWH) have persistent gastrointestinal inflammation which contributes to continued comorbidity. HIV-1 associated gut pathogenesis includes both structural and immunological changes resulting in local inflammation and increased bacterial translocation. In our prior study we observed that in PWH, higher frequencies of a serine protease called Granzyme B (GZB) were associated with greater abundance of potentially inflammatory bacteria. Moreover, enteric bacteria were shown to induce higher frequencies of GZB expressing gut CD4+ T cells. GZB is classically utilized by cytotoxic T cells to induce apoptosis but has additional functions of interest including inflammatory cytokine activation. Currently, significant gaps remain in how GZB affects inflammatory cytokine profiles in the gut. Here we aim to assess how GZB produced in response to enteric bacteria exposure drives gut associated inflammatory cytokine production in a gastrointestinal in vitro model.

### Methods
We utilized our previously established human gut lamina propria mononuclear cell (LPMCs) in-vitro model. LPMCs were stimulated with commensal Escherichia coli (E. coli) lysate in the presence of a cell permeable GZB inhibitor or extracellular anti-GZB blocking antibody. Levels of TNFα, IL-1α, IL-18, and IL-1β, which have been previously shown to be produced in response to exposure to granzymes, were measured by ELISA. Measurement after 48 hours was determined to be the optimal observation time. 

### Results
Exposure of LPMC’s to E. coli for 48 hours induced significantly higher levels of secreted GZB with measurable activity compared to LPMCs that were not exposed to E. coli. Secreted TNFα, IL-1α, IL-18, and IL-1β, and cell associated IL-1α were also increased. In the presence of cell permeable GZB inhibitor, intracellular and extracellular GZB activity was significantly inhibited, and cytokine production decreased to levels similar to unstimulated conditions. In the presence of extracellular anti-GZB blocking antibody, only extracellular GZB activity was significantly inhibited, however E. coli stimulated cytokine production was not reduced.

### Conclusion
Simultaneously blocking of both extracellular and intracellular GZB activity in response to E. coli stimulation of LPMCs in-vitro resulted in decreased production of inflammatory cytokines while inhibition of exclusively extracellular GZB did not attenuate production. This suggests that intracellular GZB, either produced or taken up by immune cell populations is the primary driver for enhancing microbe-induced inflammatory cytokine production within gut LPMCs. Treatments targeting intracellular Granzyme B function could be used in the future to better prevent and control inflammatory gut conditions.


AMA Research Challenge 2025 

The Role of Granzyme B on Inflammatory Cytokine Production by Human Gut Lamina Propria Mononuclear Cells

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technical paper

### Background
Ulcerative colitis (UC) is a chronic, relapsing and remitting immune mediated condition requiring long-term therapy. Moderate to severe disease is managed using steroids, sulfasalazine, thiopurines, biologicals (anti-tumor necrosis factor, anti-integrins and anti-interleukin IL 12/23) and small molecules (Janus kinase inhibitors, sphingosine-1-receptor modulators). Ustekinumab (UST) is a IgG1 monoclonal antibody acting on IL 12/23 recently authorized to treat moderate to severe UC that is not responsive to other biologic medicines. There remains an unmet need in management of UC despite growing availability of therapeutic agents. Current treatment algorithms use a standard approach for all patients, but targeted therapies are required for better outcomes. This study's goal is to determine the safety and effectiveness of UST therapy in moderate to severe UC. We also noted the clinical and endoscopic improvement with maintenance of clinical and steroid free remission across multiple databases to strengthen reproducibility. 

### Methods
This systematic review followed the Preferred Reporting Items for Systematic Review and Meta Analysis (PRISMA) 2020 guidelines. Relevant literature was retrieved from PubMed, PubMed Central, Cochrane Library, Science Direct and Google Scholar. Articles published in English within the last 5 years (2020 to 2025) were included. Quality assessment tools were applied to ensure the quality of evidence-based medicine that will be utilized to develop a conclusion and direct future review. 

### Results
The studies analysed showed a superiority of UST in induction and maintenance of remission in active, difficult to treat UC. Our findings indicate that reduction in Mayo score with improvement in C-reactive protein (CRP) and fecal calprotectin (fCal) can be used to assess a reduction in inflammatory burden and response to treatment. Histo-endoscopic mucosal healing also provides a long-term clinical assessment of reduction in disease burden. All safety events which led to drug discontinuation and malignancy were similar for UST therapy and placebo. 

### Conclusion
UST as a treatment option for moderate to severe UC can provide an alternative avenue in development of patient centric targeted therapies. Further research targets should include formulation of a standard dosing regimen and evaluation of long-term safety profile of the drug. There also remains an unmet need in comparative analysis of UST treatment with other available therapeutic options, especially biologic agents and effect on extra-intestinal manifestations.

Efficacy and Safety of Ustekinumab in Treatment of Ulcerative Colitis: A Systematic Review

### Background
African American women experience higher breast cancer mortality and are more frequently diagnosed with aggressive tumor subtypes compared to other racial and ethnic groups. Despite advances in cancer genomics, the absence of population-specific diagnostic tools contributes to persistent disparities in clinical outcomes. Circular RNAs (circRNAs) are stable, non-coding RNAs with emerging potential as non-invasive biomarkers in cancer detection and profiling. This study aims to identify tumor-associated circRNAs in African American breast cancer patients using a circRNA analysis pipeline. Discovering circRNA biomarkers specific to African American patients is a key step toward advancing precision oncology and achieving equity in cancer diagnostics and treatment.

### Methods
Serum samples from 35 breast cancer patients and 15 healthy female controls were obtained from the Prisma Health Cancer Institute Biorepository. Following cell-free RNA isolation and circRNA enrichment, full-length circRNA libraries were prepared using the circFL-seq protocol and sequenced using Oxford Nanopore long-read technology. After basecalling and adapter trimming, reads were aligned to the GRCh38 human reference genome. Differential expression analysis using edgeR identified circRNAs associated with cancer status. Expression profiles were compared to public circRNA datasets from individuals of European ancestry to assess race-associated differences. 

### Results
Differential gene expression analysis identified 11 circRNAs associated with race, 27 with tumor status, and 4 showing a race-tumor interaction, revealing race-specific differences in breast tumor biology. Among these, circRNAs from REG3A, a secreted lectin involved in inflammatory signaling and epithelial-mesenchymal transition (EMT), were upregulated in African-American tumors. REG3A drives tumor progression through STAT3 and mTOR activation. Similarly, circRNAs from REG1A, a secreted lectin involved in immune modulation, were upregulated and are linked to tumor progression and resistance to immune surveillance. CircRNAs from CTNNA2, a cell adhesion gene, were upregulated, indicating altered adhesion signaling and a potential regulatory role in tumor progression. In addition, AC011754.1, a long noncoding RNA was also differentially expressed and may contribute to race-specific tumor regulation.

### Conclusion
This study identifies a race-specific gene expression profile in African-American breast cancer involving dysregulation of immune and epithelial pathways. CircRNAs from REG1A, REG3A, CTNNA2, and AC011754.1 may act as molecular drivers of aggressive tumor phenotypes and serve as race-conscious diagnostic and therapeutic biomarkers. CircRNAs regulate gene expression by blocking microRNAs, limiting their ability to suppress targets involved in proliferation, invasion, and immune response. These findings highlight a critical gap in cancer genomics and underscores the need to integrate race-informed molecular data into precision oncology to drive equitable biomarker discovery and improve outcomes in underrepresented populations.

Uncovering Race-Specific CircRNA Biomarkers in African American Breast Cancer Patients

### Background
Prior studies suggest that patient-reported allergies (PRAs) may correlate with poorer surgical outcomes, including greater psychological distress, increased postoperative pain, and reduced mobility in orthopedic populations. However, the relationship between PRAs and outcomes after lumbar interbody fusion (LIF) remains unclear. This study evaluates the association between PRAs and postoperative pain, mobility, and functional improvement following LIF. 

### Methods
A retrospective review was conducted for patients who underwent elective LIF for degenerative spine pathology between November 2019 and January 2023. Patients were grouped by the presence of PRAs (n=242) or no known drug allergies (NKDA; n=83). Baseline demographics, psychiatric history, preoperative opioid use, and reported allergies—categorized as medical or environmental—were recorded. Primary outcomes included one-year changes in Patient-Reported Outcomes Measurement Information System (PROMIS) overall and mental health scores, and Oswestry Disability Index (ODI). Secondary outcomes included postoperative visual analog scale (VAS) pain scores and Activity Measure for Post-Acute Care (AMPAC) scores. Associations were assessed using univariate and multivariate regression models. Receiver operating characteristic (ROC) analysis evaluated the predictive value of PRA count for achieving minimal clinically important difference (MCID) in PROMIS and ODI scores. 

### Results
Patients with PRAs were more likely to be female (57%, p=0.002) and have psychiatric histories (0.9 ± 1.1 vs. 0.7 ± 1.0, p=0.02). PRA patients had greater improvement in PROMIS overall (11.5 ± 12.8 vs. 6.7 ± 10.2, p=0.048) and mental health scores (13.5 ± 18.7 vs. 6.6 ± 14.6, p=0.026). ODI improvement did not differ significantly. PRA count was not associated with VAS, AMPAC, or MCID achievement in PROMIS or ODI. Increasing fusion levels negatively impacted AMPAC scores (-1.096 per level fused, p<0.05) but not VAS. Psychiatric history reduced odds of achieving MCID for PROMIS physical and ODI scores, while preoperative opioid use had no impact on pain, mobility, or MCID outcomes. ROC analysis showed poor predictive value of PRA count for MCID (AUC <0.600).

### Conclusion
PRAs were not associated with worse outcomes following LIF. Instead, patients with PRAs experienced greater improvements in PROMIS, particularly in mental health. PRA count did not affect postoperative pain, mobility, or MCID achievement. These findings suggest that the presence or quantity of PRAs should not deter clinicians from recommending lumbar fusion surgery.


The Influence of Patient-Reported Allergies on Postoperative Mobility, Pain, and Long-Term Outcomes following Lumbar Interbody Fusion

### Background
Deep vein thrombosis (DVT) is a major healthcare burden with significant morbidity and mortality. Anticoagulation therapy is the current treatment of choice. However, this approach can sometimes lead to only partial resolution, allowing for thrombus organization. This can result in the development of post-thrombotic syndrome (PTS), a sequela of chronic DVT that includes symptoms such as limb pain, cramping, edema, stasis dermatitis, or even venous ulceration. There is currently no effective treatment for PTS, and as a consequence, it can become a lifelong problem that significantly impairs a patient’s quality of life. Here, we examine whether the local delivery of non-thermal irreversible electroporation (IRE) can impede thrombus organization and fibrosis by achieving cellular ablation and allowing time for natural thrombus resolution to occur.

### Methods
In vitro and ex vivo methods were utilized to investigate the thermal and ablative effects of IRE. A microfluidics device was seeded with neutrophils and endothelial cells to determine voltage thresholds for selective, safe ablation. Rheological analysis was conducted to evaluate the impact of IRE on blood coagulation. Porcine blood clots, generated in a syringe model, were used to assess red blood cell and fibrin architecture following IRE treatment. These models guided the optimization of IRE parameters for subsequent in vivo studies. Calibrated pulsed electric fields were then delivered locally using a tweezer-style electrode system to target acute DVT lesions induced in the femoral veins of rat and swine models. Animals were monitored for three or seven days post-treatment. Histological, immunohistochemical, and molecular analyses were performed to assess thrombus organization, vessel integrity, luminal cellularity, cytokine expression, and inflammatory or fibrotic markers following IRE-treatment.

### Results
IRE-treated blood demonstrated preserved clotting kinetics and minimal hemolysis, supporting the safety and efficacy of blood cell ablation using IRE. Histologic analysis of IRE-treated animal femoral vein segments revealed significantly reduced cellular proliferation, collagen deposition, and angiogenesis. IRE-treated tissues also exhibited lower expression of pro-fibrotic, pro-thrombogenic, and pro-coagulant markers compared to controls. Across both models, vessel wall thickness and luminal architecture remained intact, confirming the non-destructive nature of IRE, with no evidence of structural wall damage or aneurysm formation.

### Conclusion
These findings suggest that IRE may serve as a promising adjunctive therapy to anticoagulation by preventing the organization of acute thrombi into chronic DVT. This could ultimately reduce the incidence of post-thrombotic syndrome and improve long-term patient outcomes.

Non-Thermal Pulsed Electric Field Ablation of Blood Clots Reduces Fibrosis

### Background
The dorsal nerve of the clitoris (DNC) and dorsal nerve of the penis (DNP) are vital to sexual sensation, erectile function, and reproduction; however, these nerves are frequently subject to injury from tumor resections, aesthetic procedures, and female genital mutilation (FGM). Concerning FGM alone, the World Health Organization notes that approximately 6.5 million females in Europe and North America, and over 230 million females worldwide, are living with FGM. Nerve coaptation or neurotization may be warranted to restore function after dorsal nerve injury. Accordingly, close nerve size-matching is necessary to minimize the risk of fascicle loss and neuroma formation. However, little is known about the diameter of the dorsal nerves. Therefore, this study aims to describe the diameter of the DNC and DNP through gross anatomical assessment.

### Methods
A total of 101 donor bodies (51 female, 50 male) were dissected to visualize the paired dorsal nerves as they traveled inferior to the pubic bone. Dorsal nerves were photographed, and images were screened for quality. A total of 199 dorsal nerves met criteria for measurement. Nerve diameter was measured via ImageJ software. Sexual dimorphism and asymmetry were assessed by unpaired and paired t-tests, respectively. Correlation between nerve diameter and age was evaluated via Pearson’s test.

### Results
Nerve diameters were normally distributed in both females and males. The DNC diameter averaged 2.9±0.6mm (mean ± SD) (min=1.5mm; max=4.9mm; range=3.4mm) and the DNP averaged 3.6±0.6mm (min=1.6mm; max=5.1mm; range=3.5mm). Significant differences were found between sexes (t=7.647; p<.00001); however, within-sex, no significant side-to-side difference was identified (females: t=0.6278; p=0.5332) (males: t=1.206; p=0.2337). Age was not correlated with nerve size (r=0.17; p=0.248). Although generally symmetrical, bilateral asymmetry of up to 1.7mm in females and 1.5mm in males was noted.

### Conclusion
This report details DNC and DNP size from the largest sample population to date. Surgeons should anticipate dorsal nerve size differences between sexes, wide size variation within-sex, and possible bilateral asymmetry. These results, assessed alongside other reports, suggest that commonly grafted nerves are generally more size-compatible with the DNC as compared to the relatively larger DNP. Regarding unilateral graft procedures, such as an ilioinguinal nerve coaptation, asymmetry may influence the side upon which the procedure is performed. The results of this study will improve genital reconstruction procedures and guide optimal nerve graft selection for dorsal nerve repair.

Dorsal Nerve of the Clitoris and Dorsal Nerve of the Penis Size: Implications for Reconstruction

### Background
Executive dysfunction in Alzheimer’s disease (AD)—often linked to early frontal lobe involvement—can impair real-world behavior even during the mildest stages, well before memory loss becomes disabling. Yet many clinicians delay supervision planning until patients reach moderate dementia, overlooking critical safety risks in earlier phases. High misdiagnosis rates in early dementia further delay appropriate intervention, especially when subtle but meaningful executive deficits go undetected. Although tools like the Mini-Mental State Examination and Trails B assess cognition, none directly evaluate whether a patient can live safely without supervision. The Test of Executive Functioning in an Emergency (TEFE), developed at UNT Health, addresses this gap. TEFE is a brief, performance-based tool that assesses whether patients can complete real-world safety tasks—such as dialing 911, stating their address, and contacting a family member. This study examined whether TEFE performance—particularly on the 911 task—can differentiate mild AD from vascular dementia (VD), mixed dementia, and mild cognitive impairment (MCI), while also identifying clinically meaningful patterns of executive dysfunction across diagnoses.

### Methods
We retrospectively reviewed records of 908 patients from a university-affiliated memory clinic. Diagnoses included mild AD, mild VD, mild mixed dementia, mild cognitive impairment (MCI), or normal cognition. TEFE includes six items total: three knowledge-based questions (e.g., “What number do you call in an emergency?”) and three behavioral tasks (e.g., dialing 911). Total TEFE scores were compared across diagnostic groups using Kruskal-Wallis and chi-square tests. We further analyzed failure rates on the 911 knowledge and behavioral items individually and used contingency tables to examine disconnects between knowing and performing the task (e.g., correctly identifying 911 but failing to dial it).

### Results
TEFE performance significantly differed by diagnosis (H = 215.73, p < 1×10−44). AD patients scored significantly lower than MCI or cognitively normal groups. Nearly one-quarter of AD patients failed the 911 knowledge (24.1%) and behavioral (27.0%) tasks. In contrast, 911 failure was rare in non-AD groups—under 6% in MCI and 0% in normal controls. Chi-square tests confirmed AD patients were significantly more likely to fail 911 tasks than VD or mixed dementia (p < 0.001). Only AD patients exhibited a disconnect of identifying 911 but failing to dial it.

### Conclusion
TEFE effectively detects executive dysfunction and emergency readiness deficits in mild AD, identifying safety risks not captured by traditional cognitive screens. By revealing real-world impairments before more obvious cognitive decline, TEFE offers actionable insight that help guide earlier interventions in dementia care.

Test of Executive Function in an Emergency: A Real-World 911 Tool That Differentiates Mild Alzheimer’s Disease from Other Dementias

### Background
Patient-reported outcomes (PROMs) are standardized questionnaires patients complete to gather information concerning health outcomes, symptoms, and functional status. Prior studies have evaluated completion and/or participation rate across orthopaedic subspecialties. However, few have evaluated both completion and participation outcomes in joint replacement patients specifically. This study aims to determine the association between sociodemographic factors and PROMs completion and participation rates. 

### Methods 
A retrospective chart review was conducted of all patients who underwent primary total knee and total hip replacements by at a Midwestern, tertiary health system in 2023. PROMs used in this analysis included PROMIS PF, PROMIS PI, and either HOOS or KOOS JR. Demographic variables and PROMs completion were recorded, and the Area Deprivation Index (ADI), a measure of socioeconomic disadvantage, was determined using patients’ address. Patients were considered to participate if they filled out at least one questionnaire before and after surgery and were considered to complete PROMs if they filled out all pre- and postoperative questionnaires. Logistical regressions were performed to identify factors associated with PROMs participation and completion. 

### Results 
646 patients were included in our analysis, of which 31 (4.8%) completed all PROMs and 529 (82%) participated in PROMs. In univariate analysis, Black patients had significantly lower odds of PROMs participation (56% lower, p<0.001), as were older patients (OR 0.97; p = 0.004) and patients living in zip codes with high national ADI (OR 0.98; p < 0.001), while married patients were more likely to participate (OR 1.89, p=0.015). In the multivariable model, older age (OR 0.97, p=0.004) and Black race (OR 0.38, p=0.013) were associated with lower participation. Univariate analysis of PROMs completion suggested 69% lower likelihood among Black patients (p=0.056) and with additional preoperative visits (69% lower per day, p<0.001).

### Conclusion 
Sufficient sociodemographic representation in PROMs is necessary to determine equitable outcomes amongst all members of society. Our data is consistent with established literature with regards to how ADI and age influence PROM completion. Further exploration regarding the factors behind low PROM completion is needed in order to ensure adequate representation in orthopaedic outcomes in clinical and research environments.

Socioeconomic Impact on Patient-Report Outcome Measures Participation in Arthroplasty Patients

### Background
Total Knee Arthroplasty (TKA) is a beneficial procedure in orthopedics, but malpositioning of the femoral TKA component can cause dissatisfaction or failure. Most existing research focuses on coronal and rotational positioning, making positioning in the sagittal plane relatively unexplored. The objective of this systematic review is to determine whether variations in femoral component sagittal alignment (flexion or extension positioning) influence patient-reported outcomes, range of motion, anterior knee pain, component loosening, and prosthesis survival.

### Methods
This systematic review was performed according to the guidelines of the Preferred
Reporting Items for Systematic Review and Meta-Analyses (PRISMA) protocols (PROSPERO ID number: CRD420251044455). A comprehensive search of PubMed, Cochrane Library databases, and SPORTDiscus was performed between January 2015 and April 2025. Keywords included Total Knee Arthroplasty, Revision Total Knee Arthroplasty, Femoral Component, Sagittal Alignment, Femoral Flexion Angle, Extension Alignment, Posterior Condylar Offset, and Patient-Reported Outcome Measures. After screening 2137 initial results, 10 studies were deemed to meet inclusion and exclusion criteria, with 9 being prospective/retrospective cohort studies and 1 Randomized Control Trial (RCT). Study characteristics and outcomes were extracted, and quality assessment performed for using Cochrane Risk of Bias tool (RCTs) and Newcastle-Ottawa Scale (cohort studies).

### Results
A total of 5,205 TKAs were performed among the 10 studies, each with different sagittal alignment grouping thresholds and functional outcome scales. 5/10 studies identified the optimal sagittal alignment to be approximately 1-4° flexion for OKS, WOMAC, KSFS, or KSS functional scores, while 1 study found slightly improved AKSS with 1–5° extension. 2 studies did not identify optimum femoral angles for functional score outcomes. For ROM, 5/10 studies identified the optimum sagittal angle for ROM to be 1-7° flexion. Only 2 studies explored failure rate, with 1 study reporting the best failure rate (0%) in neutral alignment 0-3° and the other stating no cases of loosening at 1 year for any group. Anterior knee pain was only reported by 1 study with best outcomes at 1.4° flexion.

### Conclusion
Of the 10 studies, mild sagittal flexion (1-4°) appears to appropriately balance functional outcomes, ROM, survival, and pain. However, the heterogeneity of the included studies in terms of grouping measurement as well as functional outcomes precluded our ability to conduct a meta-analysis and generate exact quantitative outcomes as to the optimal sagittal alignment of the femoral component. More RCTs are needed to explore sagittal component positioning with consistent femoral flexion angle grouping criteria and clinical outcome measurements.

Mild flexion of the femoral component sagittal alignment in TKA may improve long-term clinical outcomes and component survival: A systematic review

### Background
Acute appendicitis is the most common cause of emergency general surgery in the United States and affects 250,000 adults every year. Readmission after appendectomy is common and represents an opportunity to improve care. We aimed to identify factors associated with 90-day readmission in patients with acute appendicitis to inform patient risk stratification. 

### Methods
We conducted a retrospective chart review of the emergency general surgery registry for patients with acute appendicitis between March 1, 2023, and August 31, 2024, at three hospitals within our healthcare system: one academic (H1) and two community (H2 and H3). Our primary outcome was 90-day hospital readmission. We used descriptive statistics and multivariable logistic regression to assess factors related to readmission, performed a sensitivity analysis excluding early readmissions (<7 days), and stratified models by hospital to evaluate site-level variation. 

### Results
522 patients with acute appendicitis were included; the overall 90-day readmission rate was 13.0%. Readmitted patients were on average older (56 vs 45 years, p<0.001), had higher Charlson Comorbidity Index scores (CCI) (2.1 vs. 1.2, p<0.001), and more often presented with perforated appendicitis (51% vs. 24%, p<0.001). In multivariable regression, operative management was independently associated with reduced odds of readmission (aOR 0.26, 95% CI 0.12–0.53). CCI (aOR 1.25, 95% CI 0.97–1.59) and diabetes (aOR 1.89, 95% CI 0.91–3.93) increased risk but were not statistically significant. Age, perforation status, and discharge disposition were not significant predictors of 90-day readmission. In sensitivity analysis (n=461), CCI (aOR 1.32, 95% CI 1.01–1.72) and ASA score (aOR 2.23, 95% CI 1.03–4.87) were significant predictors, while operative management remained protective (aOR 0.12, 95% CI 0.06–0.25). Older age was associated reduced readmission (aOR 0.95, 95% CI 0.91–0.99), and diabetes was not significant. Hospital-stratified analysis showed operative management was consistently protective across sites (H1 aOR 0.23, 95% CI 0.09–0.64; H2 aOR 0.04, 95% CI 0.009–0.21; H3 aOR 0.05, 95% CI 0.002–1.21). 

### Conclusion
Operative management of acute appendicitis was independently protective against 90-day readmission. Higher CCI and ASA scores increased readmission risk, particularly in patients readmitted beyond 7 days post discharge. These findings highlight the importance of individualized risk stratification, particularly in older comorbid adults, and may inform discharge planning and follow-up strategies.

Factors Affecting 90-Day Readmission After Acute Appendicitis Within a Large Healthcare System

### Background
Hypertensive diseases of pregnancy (HDP) like preeclampsia lead to fetal growth restriction (FGR), where elevated thromboxane A2 (TXA2) levels trigger maternal hypertension, recurrent placental ischemia/reperfusion injury, and fibrosis leading to placental insufficiency and FGR. We recently demonstrated a mechanistic link between procoagulant platelets and neutrophils in the innate immune response to ischemia/reperfusion injury following ischemic stroke - neutrophil extracellular trap (NET) formation. To respond to infection or tissue damage, a subset of neutrophils form NETs. These NETs release lattices of decondensed chromatin decorated with antimicrobial factors into the extracellular space. In ischemic stroke, procoagulant platelets induce NET formation leading to pathogenic inflammation which extends infarct size and compromises neurologic recovery after stroke. In the preclinical stroke model, we showed that Cyclophilin-D (CypD) induces procoagulant platelet formation which induced NETs leading to pathogenic inflammation. However, whether procoagulant platelets and NETs mediate FGR in HDP-related placental insufficiency remains unknown. We hypothesized that platelet-specific Cyclophilin D knockout (CypDplt-/-) mice exhibit decreased FGR and placental NET formation compared to wild-type (WT) mice in a preclinical model of HDP.

### Methods
Pregnant CypDplt-/- and WT mice received a TXA2 analog (U46619; 4 μg/μL at 0.5 μL/hr continuous infusion) or vehicle control (0.5 μL/hr) via micro-osmotic pumps implanted on embryonic day (E) 12.5. At E19, we measured fetal/placental weights and collected pup plasma. We assessed placental NETs and neutrophil levels via Western blotting of placental homogenates for citrullinated histone H3 (citH3) and myeloperoxidase (MPO), respectively. We assessed pup plasma MPO-DNA complex levels as a surrogate for plasma NET levels using an in-house MPO-DNA ELISA.

### Results
Compared to TXA2-treated WT pups, TXA2-treated CypDplt-/- pups showed decreased body weight at E19 (p<0.05), decreased percentage FGR (18% versus 71%), reduced placental MPO (p<0.05), with a trend towards decreased placental citH3 (p=0.051) via western blotting, suggesting decreased placental neutrophils and NETs, respectively, and decreased plasma MPO-DNA complex levels, a surrogate for NET formation (p<0.05). Finally, using a novel NET-inhibitory peptide which we discovered, we demonstrated that NET inhibition in this pre-clinical model decreased FGR in response to TXA2 treatment, a finding correlated with decreased placental (p<0.05) and plasma NET levels (p<0.05), respectively.

### Conclusion
CypDplt-/- TXA2-treated pups show decreased FGR and decreased placental NETs in a preclinical HDP model suggesting that procoagulant platelets trigger platelet activation and NET formation in HDP. Further, NET inhibition may represent a novel therapeutic target to decrease fetal growth restriction in human HDP.





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