The impact of heparin and direct thrombin inhibitors on cell-penetrating polymer siRNA transfection.

Gene therapy using siRNA has become a promising strategy to achieve targeted gene knockdown for treatment of cardiovascular pathologies. However, efficient siRNA transfection often relies on cationic delivery vectors such as synthetic cell-penetrating polymers which are susceptible to interference by negatively charged molecules. Anticoagulants such as heparin, which is negatively charged and widely used in cardiovascular applications, may pose a significant barrier to effective siRNA delivery. We therefore conducted in vitro studies utilizing human smooth muscle and endothelial cells transfected with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and ß2-microglobulin (B2M) siRNA in the presence of heparin, argatroban, and bivalirudin in order to determine which anticoagulant therapy is most compatible for siRNA delivery. We observed that while heparin, at clinical doses, decreases the efficiency of siRNA targeted mRNA knockdown, mRNA knockdown is not inhibited in the presence of either argatroban or bivalirudin. Our data suggests that heparin should be avoided during siRNA therapy with cationic transfection agents, and argatroban and bivalirudin should be used in its stead.

Utility of Torso Imaging for Elderly Patients Sustaining Ground-Level Falls.

INTRODUCTION: Computed tomography (CT) of the torso has become increasingly common for assessment of fall patients in the emergency department. Some data suggest that older adults (≥65) may benefit from torso imaging more than younger patients. We sought to evaluate the usage and utility of CT imaging for elderly patients presenting after ground-level falls (GLFs) from 1 meter or less at our level 1 trauma center. METHODS: Patients ≥18 presenting with GLF in 2015-2019 were included. Data were obtained through chart and trauma registry review. Descriptive statistics were used to summarize the use of CT imaging for patients younger than versus older than 65 y old. Three multivariate logistic regression models with age as a continuous, binary (<65 versus ≥65), or categorical (in multiples of 5) variable were used to investigate whether age is associated with an increased identification of traumatic injury not previously suspected or known based on physical exam (PE) or plain radiograph after GLF. RESULTS: A total of 522 patients <65 and 673 patients ≥65 y old were included. Older patients were significantly more likely to receive screening chest radiograph, screening pelvic radiograph, brain CT, and neck CT (all P < 0.001), but not torso (chest, abdomen, and pelvis) CT (P = 0.144). On multivariate logistic regression, age was not significantly associated with an increased odds of identification of traumatic injury after torso CT (continuous: adjusted odds ratio [aOR] = 1.01, 95% confidence interval [CI] = 0.99-1.03, P = 0.379; binary: aOR = 0.86, 95% CI = 0.46-1.58, P = 0.619; categorical: aOR = 1.03, 95% CI = 0.94-1.14, P = 0.453). A positive PE was the only variable associated with significantly increased odds of having an abnormal torso CT scan in all models. Only two patients ≥65 y old had injuries identified on torso CT in the context of a negative PE and negative screening imaging. CONCLUSIONS: The rate of torso injury identification in patients sustaining GLF is not associated with age, but is strongly associated with positive PE findings. In the subset of elderly GLF patients without positive torso PE findings, more conservative use of CT imaging could decrease health-care utilization costs without compromising patient care.

Patients Experience Significant Long-Term Social and Health Challenges After Major Lower Extremity Amputation.

BACKGROUND: Major lower extremity amputation is a significant life-changing event that can have long-term implications. The goal of this study was to assess long-term medical outcomes and social determinants of health (SDH) challenges in this population. METHODS: A retrospective review of major lower extremity (previously mentioned ankle) amputations (2018-2022) was performed at a safety-net tertiary care center. Patients who participated in an SDH survey between 6 months and 1.5 years postoperatively were included for survey analysis. Patient demographics, comorbidities, and perioperative and long-term outcomes were analyzed. RESULTS: There were 100 patients included. Mean age was 61.5 years and 23% were of female gender. The majority (57%) were Black race, 20% White race, and 21% Hispanic ethnicity. Comorbidities included diabetes (78%), chronic kidney disease (51%), coronary artery disease (31%), congestive heart failure (23%), previous cerebrovascular events (19%), and 37% used opioids preadmission. At baseline, the majority (62%) lived at home. Guillotine amputation was performed in 24%, with definitive amputation in the following and previously mentioned knee in 67% and 33%, respectively. Median length of stay was 7 days. Readmission at 30 days, 90 days, and 1 year was 13%, 30%, and 43% respectively. The average follow up was 839 days. At long-term follow up, 55% lived at home, 25% used opioids, and only 25% were independently ambulatory. In the SDH survey at follow up, 32% identified at least one SDH challenge, with younger patients more often affected (58 vs. 63 years, P = 0.031). SDH challenges consisted of food insecurity (17%), housing insecurity (13%), transportation challenges (13%), seeking employment (8%), difficulty paying for utilities (5%) and medications (4%), seeking further education (5%), and difficulty caring for family/friends (4%). On multivariable analysis, having at least one SDH challenge was independently associated with 1-year readmission (odds ratio 6.7, 95% confidence interval 1.3-35.8, P < 0.001). Older age was associated with lower long-term independent ambulation (odds ratio 0.92, 95% confidence interval 0.85-0.99, P = 0.025). CONCLUSIONS: After major lower extremity amputation, patients have significant medical and social challenges with fewer living at home, the majority were not independently ambulatory, and one-third having at least one SDH challenge. Improvements in long-term support including medical, social, and rehabilitation services are required for this vulnerable population.

Early Kidney Transplantation or Conversion to Peritoneal Dialysis after First-Time Arteriovenous Access Creation.

BACKGROUND: After autogenous arteriovenous (AV) access creation for end-stage renal disease, a majority of patients will continue on hemodialysis (HD), a minority will receive definitive treatment with kidney transplantation, and a subset of patients will convert to peritoneal dialysis (PD). Our goal was to identify patient factors associated with early transition from HD to either kidney transplantation or PD. METHODS: This is a case-control study of all patients with first-time AV access creation in the Vascular Quality Initiative (2011-2022) who had long-term follow-up. Patients who remained on HD after AV access creation were the control group while patients who received early kidney transplant or who converted to PD were the 2 case groups. Relationship among demographics, comorbidities, neighborhood social disadvantage, and functional status as they relate to renal replacement therapy modality was assessed. RESULTS: There were 19,782 patients included; the average age was 62 ± 15 years and 57% were male. During the follow-up period of a median 306 (71-403) days, 1.3% underwent a kidney transplantation and 2.3% underwent conversion to PD. On univariable analysis, rates of kidney transplantation or conversion to PD varied with race (P < 0.001), insurance status (P < 0.001), area deprivation index (ADI) quintile (P < 0.001), and several medical comorbidities. On multivariable analysis, impaired ambulation, current smoking, Medicaid or Medicare insurance, Black race, heart failure, body mass index, and older age were associated with decreased transplantation rates. Conversion to PD was associated with ADI Q5, Q4, and Q3. Decreased conversion to PD was associated with impaired ambulation, Hispanic ethnicity, Black race, former smoking, medication-controlled diabetes, and older age. CONCLUSIONS: Decreased kidney transplantation was associated with Black race and noncommercial health insurance but not ADI quintile, suggesting disparities exist beyond community-level access to care. Early kidney transplantation conveyed a 3-year survival benefit compared with HD and PD, which had similar survival. Furthermore work is required to increase access to kidney transplantation and PD.

Perivascular CLICK-gelatin delivery of thrombospondin-2 small interfering RNA decreases development of intimal hyperplasia after arterial injury.

Bypass graft failure occurs in 20%-50% of coronary and lower extremity bypasses within the first-year due to intimal hyperplasia (IH). TSP-2 is a key regulatory protein that has been implicated in the development of IH following vessel injury. In this study, we developed a biodegradable CLICK-chemistry gelatin-based hydrogel to achieve sustained perivascular delivery of TSP-2 siRNA to rat carotid arteries following endothelial denudation injury. At 21 days, perivascular application of TSP-2 siRNA embedded hydrogels significantly downregulated TSP-2 gene expression, cellular proliferation, as well as other associated mediators of IH including MMP-9 and VEGF-R2, ultimately resulting in a significant decrease in IH. Our data illustrates the ability of perivascular CLICK-gelatin delivery of TSP-2 siRNA to mitigate IH following arterial injury.

High Prevalence of Adverse Social Determinants of Health in Dialysis Access Creation Patients in a Safety-Net Setting.

BACKGROUND: Patients receiving dialysis access surgery are often exposed to adverse social determinants of health (SDH) that negatively impact their care. Our goal was to characterize these factors experienced by our arteriovenous dialysis access patients and identify differences in health outcomes based on their SDH. METHODS: We performed a retrospective cohort study of all patients who underwent dialysis access creation (2017-2021) and were screened for SDH at a clinical visit (using THRIVE survey) implemented at an urban, safety-net hospital institution within 1 year of access creation. Demographics, procedural details, early postoperative outcomes, survey responses, and referral to our hospital's preventive food pantry were recorded. Univariable analysis and multivariable analyses were performed to assess for associations with key health outcomes. RESULTS: There were 190 patients who responded to the survey within 1 year of their operation. At least 1 adverse SDH was identified in 42 (22%) patients. Normalized to number of respondents for each question, adverse SDH identified were difficulty obtaining transportation to medical appointments (18%), food insecurity (16%), difficulty affording utilities (13%), difficulty affording medication (12%), unemployed and seeking employment (9%), unstable housing (7%), difficulty caring for family/friends (6%), and desiring more education (5%). There were 71 (37%) patients who received food pantry referrals. Mean age was 60 years and 38% of patients were female and 64% were Black. More than half of patients (57%) had a tunneled dialysis catheter (TDC) at the time of access creation. Dialysis accesses created were brachiocephalic (39%), brachiobasilic (25%), radiocephalic fistulas (16%), and arteriovenous grafts (14%). Thirty-day emergency department (ED) visits, 30-day readmissions, and 90-day mortality occurred in 23%, 21%, and 2%, respectively. On univariable and multivariable analyses, any adverse SDH determined on survey and food pantry referral were not associated with preoperative dialysis through TDCs, receiving nonautogenous dialysis access, 30-day ED visits and readmissions, or 90-day mortality. CONCLUSION: Nearly a quarter of dialysis access surgery patients at a safety-net hospital experienced adverse SDH and more than one-third received a food pantry referral. Most common difficulties experienced include difficulty obtaining transportation to medical appointments, food insecurity, and difficulty paying for utilities and medication. Although there were no differences in postoperative outcomes, the high prevalence of these adverse SDH warrants prioritization of resources in this population to ensure healthy equity and further investigation into their effects on health outcomes.