Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and Reveal Durable Humoral Immunity.

We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.

CD163+ Macrophages Induce Endothelial-to-Mesenchymal Transition in Atheroma.

BACKGROUND: Cell phenotype switching is increasingly being recognized in atherosclerosis. However, our understanding of the exact stimuli for such cellular transformations and their significance for human atherosclerosis is still evolving. Intraplaque hemorrhage is thought to be a major contributor to plaque progression in part by stimulating the influx of CD163+ macrophages. Here, we explored the hypothesis that CD163+ macrophages cause plaque progression through the induction of proapoptotic endothelial-to-mesenchymal transition (EndMT) within the fibrous cap. METHODS: Human coronary artery sections from CVPath's autopsy registry were selected for pathological analysis. Athero-prone ApoE-/- and ApoE-/-/CD163-/- mice were used for in vivo studies. Human peripheral blood mononuclear cell-induced macrophages and human aortic endothelial cells were used for in vitro experiments. RESULTS: In 107 lesions with acute coronary plaque rupture, 55% had pathological evidence of intraplaque hemorrhage in nonculprit vessels/lesions. Thinner fibrous cap, greater CD163+ macrophage accumulation, and a larger number of CD31/FSP-1 (fibroblast specific protein-1) double-positive cells and TUNEL (terminal deoxynucleotidyl transferase-dUTP nick end labeling) positive cells in the fibrous cap were observed in nonculprit intraplaque hemorrhage lesions, as well as in culprit rupture sections versus nonculprit fibroatheroma sections. Human aortic endothelial cells cultured with supernatants from hemoglobin/haptoglobin-exposed macrophages showed that increased mesenchymal marker proteins (transgelin and FSP-1) while endothelial markers (VE-cadherin and CD31) were reduced, suggesting EndMT induction. Activation of NF-κB (nuclear factor kappa ß) signaling by proinflammatory cytokines released from CD163+ macrophages directly regulated the expression of Snail, a critical transcription factor during EndMT induction. Western blot analysis for cleaved caspase-3 and microarray analysis of human aortic endothelial cells indicated that apoptosis was stimulated during CD163+ macrophage-induced EndMT. Additionally, CD163 deletion in athero-prone mice suggested that CD163 is required for EndMT and plaque progression. Using single-cell RNA sequencing from human carotid endarterectomy lesions, a population of EndMT was detected, which demonstrated significant upregulation of apoptosis-related genes. CONCLUSIONS: CD163+ macrophages provoke EndMT, which may promote plaque progression through fibrous cap thinning.

Interruption of Insurance Coverage and the Risk of Amputation in Patients with Pre-Existing Commercial Health Insurance and Peripheral Artery Disease.

BACKGROUND: Peripheral artery disease (PAD) is linked with an increased risk of lower extremity amputation and multiple socioeconomic factors attenuate this risk. Prior studies have demonstrated increased rates of amputation in PAD patients with suboptimal or no insurance coverage. However, the impact of insurance loss in PAD patients with pre-existing commercial insurance coverage is unclear. In this study, we evaluated the outcomes of PAD patients who lose commercial insurance coverage. METHODS: The Pearl Diver all-payor insurance claims database was used to identify adult patients (>18 years) with a PAD diagnosis from 2010 to 2019. The study cohort included patients with pre-existing commercial insurance and at least 3 years continuous enrollment after diagnosis of PAD. Patients were stratified based on whether they had an interruption of commercial insurance coverage over time. Patients who transitioned from commercial insurance to Medicare and other government-sponsored insurance during follow up were excluded. Adjusted comparison (1:1 ratio) was performed using propensity matching for age, gender, the Charlson Comorbidity Index (CCI), and relevant comorbidities. The main outcomes were major amputation and minor amputation. Cox proportional hazards ratios and Kaplan-Meier estimate were used to examine the association between loss of insurance and outcomes. RESULTS: Among the 214,386 patients included, 43.3% (n = 92,772) had continuous commercial insurance coverage and 56.7% (n = 121,614) had interruption of coverage (transition to uninsured or Medicaid coverage) during follow up. In the crude cohort and matched cohort, interruption of coverage was associated with lower major amputation-free survival on Kaplan Meier estimate (P < 0.001). In the crude cohort, interruption of coverage was associated with 77% increased risk of major amputation (OR 1.77, 95% CI 1.49-2.12) and a 41% high risk of minor amputation (OR 1.41, 95% CI 1.31-1.53). In the matched cohort, interruption of coverage was associated with 87% increased risk of major amputation (OR 1.87, 95% CI 1.57-2.25) and a 104% increased risk of minor amputation (OR 1.47, 95% CI 1.36-1.60). CONCLUSIONS: Interruption of insurance coverage in PAD patients with pre-existing commercial health insurance was associated with increased risks of lower extremity amputation.

Extracranial carotid atherosclerosis is associated with increased neurofibrillary tangle accumulation.

OBJECTIVE: We sought to determine whether extracranial carotid atherosclerotic disease (ECAD) is associated with increased key neurodegenerative pathology such as neurofibrillary tangle (NFT), beta-amyloid plaque, or cerebral amyloid angiopathy (CAA) accumulation, findings associated with Alzheimer's disease (AD) and other dementias. METHODS: Our prospective, longitudinal, clinicopathologic study, the AZSAND (Arizona study of aging and neurodegenerative disorders) and Brain and Body Donation Program, recorded the presence or absence of clinically diagnosed ECAD and performed semiquantitative density estimates of NFT, beta-amyloid plaque, and CAA at death. After adjusting for potential confounding factors determined by logistic regression analysis, histopathology density scores were evaluated in individuals with ECAD (n = 66) and those without ECAD (n = 125). RESULTS: We found that the presence of ECAD was associated with a 21% greater NFT burden at death compared with no ECAD (P = .02). Anatomically, an increased NFT burden was seen throughout the brain regions evaluated but was significant in the temporal lobe (P < .05) and entorhinal cortex (P = .02). In addition, we found that subjects who had undergone carotid endarterectomy (CEA), the surgical treatment of ECAD (n = 32), had decreased NFT densities compared with those with ECAD who had not undergone CEA (n = 66; P = .04). In contrast to NFT, ECAD was not associated with beta-amyloid plaques or CAA density. CONCLUSIONS: These findings indicate that ECAD is associated with the NFT burden in the temporal lobe and entorhinal cortex, which has clinical significance for AD and non-AD dementias and cognitive dysfunction. Further understanding of whether ECAD increases the risk of neurodegenerative brain changes is highly relevant because ECAD is a treatable disease that has not, otherwise, been evaluated for nor specifically treated as a dementia risk factor.

Economic value of podiatry service in limb salvage alliance.

OBJECTIVE/BACKGROUND: Over the past decade, multidisciplinary "toe and flow" programs have gained great popularity, with proven benefits in limb salvage. Many vascular surgeons have incorporated podiatrists into their practices. The viability of this practice model requires close partnership, hospital support, and financial sustainability. We intend to examine the economic values of podiatrists in a busy safety-net hospital in the Southwest United States. METHODS: An administrative database that captured monthly operating room (OR) cases, clinic encounters, in-patient volume, and total work relative value units (wRVUs) in an established limb salvage program in a tertiary referral center were examined. The practice has a diverse patient population with >30% of minority patients. During a period of 3 years, there was a significant change in the number of podiatrists (from 1 to 4) within the program, whereas the clinical full-time employees for vascular surgeons remained relatively stable. RESULTS: The limb salvage program experienced >100% of growth in total OR volumes, clinic encounters, and total wRVUs over a period of 4 years. A total of 35,591 patients were evaluated in a multidisciplinary limb salvage clinic, and 5535 procedures were performed. The initial growth of clinic volume and operative volume (P < .01) were attributed by the addition of vascular surgeons in year one. However, recruitment of podiatrists to the program significantly increased clinic and OR volume by an additional 60% and >40%, respectively (P < .01) in the past 3 years. With equal number of surgeons, podiatry contributed 40% of total wRVUs generated by the entire program in 2019. Despite the fact that that most of the foot and ankle procedures that were regularly performed by vascular surgeons were shifted to the podiatrists, vascular surgeons continued to experience an incremental increase in operative volume and >10% of increase in wRVUs. CONCLUSIONS: This study shows that the value of close collaboration between podiatry and vascular in a limb salvage program extends beyond a patient's clinical outcome. A financial advantage of including podiatrists in a vascular surgery practice is clearly demonstrated.

Risk factors associated with microembolization after carotid intervention.

BACKGROUND: Microembolization after carotid artery stenting (CAS) and carotid endarterectomy (CEA) has been documented and may confer risk for neurocognitive impairment. Patients undergoing stenting are known to be at higher risk for microembolization. In this prospective cohort study, we compare the microembolization rates for patients undergoing CAS and CEA and perioperative characteristics that may be associated with microembolization. METHODS: Patients undergoing CAS and CEA were prospectively recruited under local institutional review board approval from an academic medical center. All patients also received 3T brain magnetic resonance imaging with a diffusion-weighted imaging sequence preoperatively and within 24 hours postoperatively to identify procedure-related new embolic lesions. Preoperative, postoperative, procedural factors, and plaque characteristics were collected. Factors were tested for statistical significance with logistic regression. RESULTS: A total of 202 patients were enrolled in the study. There were 107 patients who underwent CAS and 95 underwent CEA. Patients undergoing CAS were more likely to have microemboli than patients undergoing CEA (78% vs 27%; P < .0001). For patients undergoing CAS, patency of the external carotid artery (odds ratio [OR], 11.4; 95% confidence interval [CI], 1.11-117.6; P = .04), lesion calcification (OR, 5.68; 95% CI, 1.12-28.79; P = .04), and lesion length (OR, 0.29; 95% CI, 0.08-1.01; P = .05) were all found to be independent risk factors for perioperative embolization. These factors did not confer increased risk to patients undergoing CEA. CONCLUSIONS: Patients undergoing CAS are at higher risk for perioperative embolization. The risk for perioperative embolization is related to the length of the lesion and calcification. Identifying the preoperative risk factors may help to guide patient selection and, thereby, reduce embolization-related neurocognitive impairment.

Effect of frailty syndrome on the outcomes of patients with carotid stenosis.

BACKGROUND: Frailty syndrome confers a greater risk of morbidity and mortality after operative interventions. The aim of the present study was to assess the effect of frailty on the outcomes after carotid interventions, including both carotid endarterectomy (CEA) and carotid artery stenting (CAS). METHODS: We performed an 8-year (2005-2012) retrospective analysis of the National Surgery Quality and Improvement Program database, including patients who had undergone CEA or CAS for carotid artery stenosis. A modified frailty index score was calculated. Frail status was defined as a modified frailty index score of ≥0.27. The outcome measures were inpatient complications, mortality, failure to rescue (FTR), hospital length of stay, and 30-day readmissions. Multivariable regression analysis was performed to study the association between frailty and the perioperative outcomes. RESULTS: The data from 37,875 patients were included. Of the 37,875 patients, 95.7% had undergone CEA, and 27.3% of the patients were frail (27% of the CEA and 26% of the CAS groups had qualified as frail). Overall, 11.7% of the patients had experienced complications, 2.2% had died, and 6.7% had been readmitted after discharge. On regression analysis, after controlling for age, gender, albumin level, type of surgery, and American Society of Anesthesiologists class, frail status was an independent predictor of complications (23.5% vs 7.2%; P < .001), mortality (5.2% vs 1.1%; P = .02), FTR (12.1% vs 4.7%; P = .02), and 30-day readmissions (14.9% vs 3.7%; P = .03). On subanalysis of the patients who had undergone CAS, no association was found between frail status and the occurrence of complications (odds ratio [OR], 1.5; 95% confidence interval [CI], 0.8-3.2), mortality (OR, 1.2; 95% CI, 0.6-2.7), FTR (OR, 0.9; 95% CI, 0.4-2.3), and 30-day readmission rate (OR, 1.1; 95% CI, 0.5-3.1). CONCLUSIONS: Frailty syndrome was associated with morbidity and mortality among patients undergoing surgical interventions for carotid stenosis. In the present study, frailty was associated with significant mortality and morbidity for those who had undergone CEA but not for those who had undergone CAS. However, the present study was not designed to determine the optimal treatment of frail patients. Incorporating frailty status into the treatment algorithm (CEA vs CAS) might provide a more accurate risk assessment and improve patient outcomes.

Sensor-Based Upper-Extremity Frailty Assessment for the Vascular Surgery Risk Stratification.

BACKGROUND: Available methods for determining outcomes in vascular surgery patients are often subjective or not applicable in nonambulatory patients. The purpose of the present study was to assess the association between vascular surgery outcomes and a previously validated upper-extremity function (UEF) method, which incorporates wearable motion sensors for the physical frailty assessment. MATERIALS AND METHODS: Patients (≥50 y old) undergoing vascular surgery were recruited. Participants performed the 20-s UEF test, which involved rapid elbow flexion. This technology quantifies physical frailty features including slowness, weakness, exhaustion, and flexibility, which allows grouping individuals into nonfrail, prefrail, and frail categories. Surgical outcomes included length of hospital stay, discharged disposition, and 30-d mortality, complications, readmission, and reintervention(s). Associations between outcomes and frailty were assessed using nominal logistic regression models, adjusted for age, gender, body mass index, and wound classification. RESULTS: Thirty-seven participants were recruited: eight nonfrail (age = 62.0 ± 10.6); 22 prefrail (age = 65.6 ± 11.6); and seven frail (age = 68.0 ± 8.0). Significant associations were observed between frailty and length of hospital stay (three times longer among frail participants, P = 0.03), mortality after surgery (two incidents among frail participants, P < 0.01), and adverse discharge disposition (all nonfrail patients were discharged home, whereas only 43% of frail patients discharged home, P = 0.01). CONCLUSIONS: This is the first study to validate the utility of UEF among patients undergoing any vascular surgery. Findings suggest that UEF may provide an objective and simple approach for assessing frailty to predict adverse events after vascular surgery, especially for nonambulatory patients.

Frailty Syndrome in Patients with Carotid Disease: Simplifying How We Calculate Frailty.

BACKGROUND: Frailty syndrome is an established predictor of adverse outcomes after carotid surgery. Recently, a modified 5-factor National Surgical Quality Improvement Program frailty index has been used; however, its utility in vascular procedures is unclear. The aim of our study was to compare the 5-factor modified frailty index (mFI-5) with the 11-factor modified frailty index (mFI-11) regarding value and predictive ability for mortality, postoperative infection, and unplanned 30-day readmission. METHODS: The mFI was calculated by dividing the number of factors present for a patient by the number of available factors for which there were no missing data. Spearman rho test was used to assess the correlation between the mFI-5 and mFI-11. Predictive models, using both unadjusted and adjusted logistic regressions, were created for each outcome for carotid endarterectomy using 2005-2012 National Surgical Quality Improvement Program data, the last year all mFI-11 variables existed. RESULTS: A total of 36,000 patients were included with mean age of 74.6 ± 5.9 years, complication rate of 10.7%, mortality rate of 3.1%, and readmission rate of 6.2%. Correlation between mFI-5 and mFI-11 was above 0.9 across all outcomes for patients. mFI-5 had strong predictive ability for mortality, postoperative complications, and 30-day readmission. CONCLUSIONS: The mFI-5 and mFI-11 are equally effective predictors of postoperative outcomes in patients undergoing carotid endarterectomy. mFI-5 is a strong predictor of postoperative complications, mortality, and 30-day readmission.

An efficient 3D stack-of-stars turbo spin echo pulse sequence for simultaneous T2-weighted imaging and T2 mapping.

PURPOSE: To design a pulse sequence for efficient 3D T2-weighted imaging and T2 mapping. METHODS: A stack-of-stars turbo spin echo pulse sequence with variable refocusing flip angles and a flexible pseudorandom view ordering is proposed for simultaneous T2-weighted imaging and T2 mapping. An analytical framework is introduced for the selection of refocusing flip angles to maximize relative tissue contrast while minimizing T2 estimation errors and maintaining low specific absorption rate. Images at different echo times are generated using a subspace constrained iterative reconstruction algorithm. T2 maps are obtained by modeling the signal evolution using the extended phase graph model. The technique is evaluated using phantoms and demonstrated in vivo for brain, knee, and carotid imaging. RESULTS: Numerical simulations demonstrate an improved point spread function with the proposed pseudorandom view ordering compared to golden angle view ordering. Phantom experiments show that T2 values estimated from the stack-of-stars turbo spin echo pulse sequence with variable refocusing flip angles have good concordance with spin echo reference values. In vivo results show the proposed pulse sequence can generate qualitatively comparable T2-weighted images as conventional Cartesian 3D SPACE in addition to simultaneously generating 3D T2 maps. CONCLUSION: The proposed stack-of-stars turbo spin echo pulse sequence with pseudorandom view ordering and variable refocusing flip angles allows high resolution isotropic T2 mapping in clinically acceptable scan times. The optimization framework for the selection of refocusing flip angles improves T2 estimation accuracy while generating T2-weighted contrast comparable to conventional Cartesian imaging.

Near-instant noninvasive optical imaging of tissue perfusion for vascular assessment.

BACKGROUND: Noninvasive vascular tests are critical for identifying patients who may benefit from surgical revascularization, but current tests have significant limitations in people with diabetes. This study aimed to evaluate the ability of spatial frequency domain imaging (SFDI), an optical imaging method capable of measuring tissue oxygen saturation (StO2) and tissue hemoglobin, to assess lower extremity blood supply. METHODS: Ankle-brachial index, toe-brachial index, pedal Doppler waveforms, and SFDI images were prospectively evaluated in 47 consecutive patients with and without diabetes in whom there was concern for peripheral artery disease (PAD). SFDI is a noncontact optical imaging technology that uses structured illumination to quantify subsurface (2-3 mm in depth) StO2 and tissue hemoglobin in the dermal microcirculation (HbT1) and macrocirculation (HbT2) over a large field of view (15 × 20 cm) within 10 seconds. RESULTS: This demonstrates the ability of SFDI to capture reliable clinical measurements of perfusion in plantar aspects of the feet. SFDI StO2 values differentiate nondiabetic patients with and without arterial disease, defined as ankle-brachial index <0.9 (P = .06), but are limited in those with diabetes (P = .43). An elevated StO2 and reduced HbT1 are observed in people with diabetes compared with nondiabetic patients (P < .05). An SFDI-derived HbT2/HbT1 index differentiates diabetics with PAD vs no PAD (P < .01) using toe-brachial index <0.7 as a cutoff for PAD in diabetes. CONCLUSIONS: SFDI is a feasible, rapid, and easy to use widefield measurement of perfusion in a clinical setting. This first-of-use study suggests that the technology has potential to evaluate lower extremity perfusion in people with and without diabetes. Further studies with increased numbers of patients and end points including wound healing will need to be designed to fully evaluate the applicability of this new technology.

Length of Stay and ICU Stay Are Increased With Repair of Traumatic Superior Mesenteric Vein Injury.

BACKGROUND: Traumatic superior mesenteric vein (SMV) injury is rare, and the ideal treatment is controversial. We compared the outcomes of ligation versus repair of SMV injury using the National Trauma Databank. MATERIALS AND METHODS: All adult patients who suffered from traumatic SMV injury were identified from the National Trauma Databank (2002-2014) by International Classification of Diseases (ICD) codes. Patients were stratified by treatment modality into no repair, ligation, and surgical repair using ICD procedure codes. Patient characteristics were compared between ligation and surgical repair groups using the Kruskal-Wallis test for continuous variables and Fisher's exact test for categorical variables. Outcomes, including mortality, rates of small bowel resection, length of stay (LOS), and ventilation days were compared using logistic regression. RESULTS: Among 952 patients with SMV injury, 192 patients (20.2%) had ligation, 428 (50%) underwent surgical repair, and 332 patients (34.9%) had neither repair nor ligation of the SMV. Overall hospital mortality was 32%. Age, gender, injury severity score (ISS), and Glasgow Coma Scale (GCS) were similar between groups that underwent ligation and surgical repair. Although the mortality rate (29.4% versus 36.5%, P = 0.20) and bowel resection rate (4% versus 3%, P = 0.12) were similar, patients who underwent repair had significantly longer hospital LOS (19.4 ± 24.8 versus15.2 ± 24.4 d, P < 0.001) and ICU LOS (13 ± 17.1 versus 9.3 ± 11.8 d, P = 0.02) compared to ligation. Similar results were observed in multivariable analysis when adjusted for race, associated vascular injuries, and other associated injuries. CONCLUSIONS: In patients with traumatic SMV injury, surgical repair does not appear to confer a significant survival advantage over ligation and can be associated with greater LOS and ICU LOS. Ligation may be an acceptable option for management of a traumatic SMV injury, especially when surgical repair cannot be performed, without compromising patient mortality or bowel resection rates.

Endothelial vascular cell adhesion molecule 1 is a marker for high-risk carotid plaques and target for ultrasound molecular imaging.

BACKGROUND: Molecular imaging of carotid plaque vulnerability to atheroembolic events is likely to lead to improvements in selection of patients for carotid endarterectomy (CEA). The aims of this study were to assess the relative value of endothelial inflammatory markers for this application and to develop molecular ultrasound contrast agents for their imaging. METHODS: Human CEA specimens were obtained prospectively from asymptomatic (30) and symptomatic (30) patients. Plaques were assessed by semiquantitative immunohistochemistry for vascular cell adhesion molecule 1 (VCAM-1), lectin-like oxidized low-density lipoprotein receptor 1, P-selectin, and von Willebrand factor. Established small peptide ligands to each of these targets were then synthesized and covalently conjugated to the surface of lipid-shelled microbubble ultrasound contrast agents, which were then evaluated in a flow chamber for binding kinetics to activated human aortic endothelial cells under variable shear conditions. RESULTS: Expression of VCAM-1 on the endothelium of CEA specimens from symptomatic patients was 2.4-fold greater than that from asymptomatic patients (P < .01). Expression was not significantly different between groups for P-selectin (P = .43), von Willebrand factor (P = .59), or lectin-like oxidized low-density lipoprotein receptor 1 (P = .99). Although most plaques from asymptomatic patients displayed low VCAM-1 expression, approximately one in five expressed high VCAM-1 similar to plaques from symptomatic patients. In vitro flow chamber experiments demonstrated that VCAM-1-targeted microbubbles bind cells that express VCAM-1, even under high-shear conditions that approximate those found in human carotid arteries, whereas binding efficiency was lower for the other agents. CONCLUSIONS: VCAM-1 displays significantly higher expression on high-risk (symptomatic) vs low-risk (asymptomatic) carotid plaques. Ultrasound contrast agents bearing ligands for VCAM-1 can sustain high-shear attachment and may be useful for identifying patients in whom more aggressive treatment is warranted.

Dosage of X-linked Toll-like receptor 8 determines gender differences in the development of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a high incidence in females and a complex phenotype. Using 564Igi mice, a model of SLE with knock-in genes encoding an autoreactive anti-RNA Ab, we investigated how expression of Toll-like receptors (TLRs) in B cells and neutrophils affects pathogenesis. We established that TLR signaling through MyD88 is necessary for disease. Autoantibody was produced in mice with single deletions of Tlr7, Tlr8, or Tlr9 or combined deletions of Tlr7 and Tlr9. Autoantibody was not produced in the combined absence of Tlr7 and Tlr8, indicating that TLR8 contributes to the break in tolerance. Furthermore, TLR8 was sufficient for the loss of B-cell tolerance, the production of class-switched autoantibody, heightened granulopoiesis, and increased production of type I IFN by neutrophils as well as glomerulonephritis and death. We show that dosage of X-linked Tlr8 plays a major role in the high incidence of disease in females. In addition, we show that the negative regulation of disease by TLR9 is exerted primarily on granulopoiesis and type I IFN production by neutrophils. Collectively, we suggest that individual TLRs play unique roles in the pathogenesis of systemic lupus erythematosus, suggesting new targets for treatment.

Association of Preulcerative Foot Care and Outcomes of Diabetic Foot Ulceration.

BACKGROUND: The purpose of this study was to determine the association of preulcerative foot care and outcomes of diabetic foot ulcerations (DFUs). METHODS: This retrospective cohort study using the Mariner all-payers claims data set included participants with a new DFU from 2010 to 2019. Patients were stratified into two cohorts (foot care and control) based on whether they had received any outpatient foot care within 12 months before DFU. Adjusted comparison was performed by propensity matching for age, sex, and the Charlson Comorbidity Index (1:2 ratio). Kaplan-Meier estimates and logistic regression examined the association between foot care and outcomes of DFUs. RESULTS: Of the 307,131 patients in the study cohort, 4.7% (n = 14,477) received outpatient preulcerative foot care within the 12-month period before DFU. The rate of major amputation was 1.8% (foot care, 1.2%), and 9.0% of patients had hospitalizations for foot infection within 12 months after DFU (foot care, 7.8%). In the study cohort, patients who received pre-DFU foot care had greater major amputation-free survival (P < .001) on Kaplan-Meier estimate. In both the study and matched cohorts, multivariable analysis demonstrated that foot care was associated with lower odds of major amputation for both study (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.48-0.66) and matched (OR, 0.61; 95% CI, 0.51-0.72) cohorts, and lower odds of hospitalizations for a foot infection in both study (OR, 0.91; 95% CI, 0.86-0.96) and matched (OR, 0.88, 95% CI, 0.82-0.94) cohorts. CONCLUSIONS: Among patients with a new DFU, those who received outpatient preulcerative foot care within 12 months of diagnosis had lower risks of major amputation and hospitalizations for foot infection.

Serum detection of blood brain barrier injury in subjects with a history of stroke and transient ischemic attack.

Objective: Stroke and transient ischemic attack may have long-term negative effects on the blood-brain barrier (BBB) and promote endothelial inflammation, both of which could increase neurodegeneration and dementia risk beyond the cell death associated with the index event. Methods: Serum from 88 postmortem subjects in the Arizona Study of Aging and Neurodegenerative Disorders were analyzed by sandwich ELISA for specific biomarkers to investigate the effects of cerebrovascular accidents (CVAs) on BBB integrity and endothelial activation. Statistical analyses were performed using the Mann-Whitney U Test, Spearman rank correlation, and linear/logistic regressions adjusted for potential confounders; a P-value < .05 was considered significant for all analyses. Results: Serum PDGFRẞ, a putative biomarker of BBB injury, was significantly increased in subjects with vs without a history of CVA who had similar cardiovascular risk factors (P < .01). This difference was stable after adjusting for age, hypertension, and other potential confounders in regression analysis (odds ratio, 27.02; 95% confidence interval, 2.61-411.7; P < .01). In addition, PDGFRẞ was positively associated with VCAM-1, a biomarker of endothelial inflammation (ρ = 0.42; P < .01). Conclusions: Our data suggest that patients with stroke or transient ischemic attack have lasting changes in the BBB. Still more, this demonstrates the utility of PDGFRẞ as a serum-based biomarker of BBB physiology, a potentially powerful tool in studying the role of the BBB in various neurodegenerative diseases and COVID infection sequelae. Clinical Relevance: Our data demonstrate the utility of serum PDGFRẞ, a putative biomarker of BBB integrity in the setting of stroke and TIA (CVA). A serum biomarker of BBB integrity could be a useful tool to detect early BBB damage and allow prospective work to study how such damage affects long-term neurodegenerative risk. Since BBB disruption occurs early in ADRD development, it could be monitored to help better understand disease progression and involvement of vascular pathways in ADRD.

Innovative use of iliac branch device for repair of a type V thoracoabdominal aortic aneurysm.

In this innovative technique case report, we describe the off-label use of an iliac branch endoprosthesis and a main body endovascular aneurysm repair component for total endovascular repair of a thoracoabdominal aortic aneurysm in a patient unsuitable for open repair. In the present report, we describe case planning and measurement techniques for this type of repair and postoperative considerations. The take-home lessons include the importance of advanced planning and the overall feasibility of this technique compared with other approaches, including the snorkel technique, in select patients.

Stratification of Microvascular Disease Severity in the Foot Using Spatial Frequency Domain Imaging.

BACKGROUND: Microvascular disease (MVD) describes systemic changes in the small vessels (~100 um diameter) that impair tissue oxygenation and perfusion. MVD is a common but poorly monitored complication of diabetes. Recent studies have demonstrated that MVD: (i) is an independent risk factor for ulceration and amputation and (ii) increases risk of adverse limb outcomes synergistically with PAD. Despite the clinical relevance of MVD, microvascular evaluation is not standard in a vascular assessment. METHODS: We evaluated 299 limbs from 153 patients seen clinically for possible lower extremity PAD. The patients were assessed by ankle brachial index (ABI), toe brachial index (TBI), and spatial frequency domain imaging (SFDI). These measurements were evaluated and compared to patient MVD status, defined by clinical diagnoses of (in ascending order of severity) no diabetes; diabetes; diabetes + neuropathy; diabetes + neuropathy + retinopathy. RESULTS: SFDI-derived parameters HbT1 and StO2 were significantly different across the MVD groups (P < .001). A logistic regression model based on HbT1 and StO2 differentiated limbs with severe MVD (diabetes+neuropathy+retinopathy) from the larger group of limbs from patients with only diabetes (P = .001, area under the curve = 0.844). Neither ABI nor TBI significantly differentiated these populations. CONCLUSIONS: Standard assessment of PAD using ABI and TBI are inadequate for detecting MVD in at-risk populations. SFDI-defined HbT1 and StO2 are promising tools for evaluating MVD. Prospective studies with wound-based outcomes would be useful to further evaluate the role MVD assessment could play in routine clinical evaluation of patients at risk for lower extremity complications.

Assessment of revascularization impact on microvascular oxygenation and perfusion using spatial frequency domain imaging.

The microvasculature (with vessels <100 µm in diameter) plays a crucial role in tissue oxygenation, perfusion and wound healing in the lower limb. While this holds clinical significance, microvasculature evaluation in the limbs is not a standard practice. Surgical interventions focus on reestablishing blood flow in larger vessels affected by the peripheral artery disease (PAD). Nevertheless, the impact of revascularization on tissue oxygenation and perfusion in severe microvascular disease (MVD) is still unknown. We present the cases of two patients who underwent surgical revascularization for peripheral blood flow with different outcomes. Patient A had PAD, while B had PAD, severe MVD and a non-healing wound. Although both showed improvements in ankle-brachial index post-op, spatial frequency domain imaging metrics (which measure microvascular oxygenation and perfusion) remained unchanged in B, indicating a potential gap in assessing the surgical efficacy in MVD using ankle brachial index and emphasizing microcirculation evaluation in optimizing wound healing outcomes.

T-cell cellular stress and reticulocyte signatures, but not loss of naïve T lymphocytes, characterize severe COVID-19 in older adults.

In children and younger adults up to 39 years of age, SARS-CoV-2 usually elicits mild symptoms that resemble the common cold. Disease severity increases with age starting at 30 and reaches astounding mortality rates that are ~330 fold higher in persons above 85 years of age compared to those 18-39 years old. To understand age-specific immune pathobiology of COVID-19, we have analyzed soluble mediators, cellular phenotypes, and transcriptome from over 80 COVID-19 patients of varying ages and disease severity, carefully controlling for age as a variable. We found that reticulocyte numbers and peripheral blood transcriptional signatures robustly correlated with disease severity. By contrast, decreased numbers and proportion of naïve T-cells, reported previously as a COVID-19 severity risk factor, were found to be general features of aging and not of COVID-19 severity, as they readily occurred in older participants experiencing only mild or no disease at all. Single-cell transcriptional signatures across age and severity groups showed that severe but not moderate/mild COVID-19 causes cell stress response in different T-cell populations, and some of that stress was unique to old severe participants, suggesting that in severe disease of older adults, these defenders of the organism may be disabled from performing immune protection. These findings shed new light on interactions between age and disease severity in COVID-19.