Complement: Functions, location and implications.

The complement system, an arm of the innate immune system plays a critical role in both health and disease. The complement system is highly complex with dual possibilities, helping or hurting the host, depending on the location and local microenvironment. The traditionally known functions of complement include surveillance, pathogen recognition, immune complex trafficking, processing and pathogen elimination. The noncanonical functions of the complement system include their roles in development, differentiation, local homeostasis and other cellular functions. Complement proteins are present in both, the plasma and on the membranes. Complement activation occurs both extra- and intracellularly, which leads to considerable pleiotropy in their activity. In order to design more desirable and effective therapies, it is important to understand the different functions of complement, and its location-based and tissue-specific responses. This manuscript will provide a brief overview into the complex nature of the complement cascade, outlining some of their complement-independent functions, their effects at different locale, and their implication in disease settings.

Broad organ acceptance and equitable access to early kidney transplantation.

BACKGROUND: Broad organ acceptance can increase early kidney transplantation (KTX) within <1-year of dialysis initiation while improving access inequity. METHODS: Single-center data of adult isolated deceased-donor KTX recipients between 2013 and 2020 were stratified into three 2.5-year periods before-, early after-, and late after our center's deceased-donor organ acceptance practice change, excluding a 6-month implementation period. Outcomes were assessed within five recipient subgroups based on demographic and clinical characteristics. RESULTS: Of 704 recipients, the frequency of early KTX was 22% pre-change, 36% early post-change, and 34% late post-change. Given similar post-change frequencies of early KTX, post-change eras were combined to improve analytic power of subgroup analyses. After the organ acceptance practice change (vs. pre-change), the likelihood of early KTX increased variably within historically underserved groups, including recipients who were older (37%-39%, p = .859), Black (10%-21%, p = .136), female (21%-37%, p = .034), diabetic (13%-32%, p = .010), and BMI≥35 kg/m2 (20%-34%, p = .007). Despite the practice change, Black recipients continued to experience less early KTX compared to non-Black recipients. The likelihood of delayed graft function was significantly increased (p < .001), and 1-year creatinine was significantly higher (p < .001) post-practice change, but between-era risk-adjusted death-censored graft survival was similar. CONCLUSIONS: Transition to broader donor acceptance was associated with more early KTXs among historically underserved patient subgroups. However, the effect was non-significant among Black recipients, suggesting the need for additional strategies to impact early transplant access for this population. Studies of broad organ acceptance are needed to examine both access and outcomes.

Reperfusion Without Functional Independence in Late Presentation of Stroke With Large Vessel Occlusion.

BACKGROUND: Reperfusion without functional independence (RFI) is an undesired outcome following thrombectomy in acute ischemic stroke. The primary objective was to evaluate, in patients presenting with proximal anterior circulation occlusion stroke in the extended time window, whether selection with computed tomography (CT) perfusion or magnetic resonance imaging is associated with RFI, mortality, or symptomatic intracranial hemorrhage (sICH) compared with noncontrast CT selected patients. METHODS: The CLEAR study (CT for Late Endovascular Reperfusion) was a multicenter, retrospective cohort study of stroke patients undergoing thrombectomy in the extended time window. Inclusion criteria for this analysis were baseline National Institutes of Health Stroke Scale score ≥6, internal carotid artery, M1 or M2 segment occlusion, prestroke modified Rankin Scale score of 0 to 2, time-last-seen-well to treatment 6 to 24 hours, and successful reperfusion (modified Thrombolysis in Cerebral Infarction 2c-3). RESULTS: Of 2304 patients in the CLEAR study, 715 patients met inclusion criteria. Of these, 364 patients (50.9%) showed RFI (ie, mRS score of 3-6 at 90 days despite successful reperfusion), 37 patients (5.2%) suffered sICH, and 127 patients (17.8%) died within 90 days. Neither imaging selection modality for thrombectomy candidacy (noncontrast CT versus CT perfusion versus magnetic resonance imaging) was associated with RFI, sICH, or mortality. Older age, higher baseline National Institutes of Health Stroke Scale, higher prestroke disability, transfer to a comprehensive stroke center, and a longer interval to puncture were associated with RFI. The presence of M2 occlusion and higher baseline Alberta Stroke Program Early CT Score were inversely associated with RFI. Hypertension was associated with sICH. CONCLUSIONS: RFI is a frequent phenomenon in the extended time window. Neither magnetic resonance imaging nor CT perfusion selection for mechanical thrombectomy was associated with RFI, sICH, and mortality compared to noncontrast CT selection alone. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04096248.

Anticoagulation Therapy in a Patient who had two Consecutive Strokes After Antibiotic Therapy for Infective Endocarditis: A Case Report.

A 77-year-old male presented with altered mentation and was diagnosed with infective endocarditis. Echocardiography revealed aortic valve vegetations. While receiving inpatient antibiotic therapy, the patient experienced an acute ischemic stroke. Magnetic resonance imaging of the brain showed punctate embolic-appearing infarcts in the right cerebellum and in the left occipital, frontal, and parietal lobes. Anticoagulation was not initiated due to a high risk of hemorrhagic transformation. He was readmitted after being discharged due to another episode of altered mentation. Repeat echocardiography indicated increased size of aortic valve vegetations. The patient was then transferred to our hospital for surgical intervention of enlarging vegetations, however was deemed unsuitable for surgery. During hospitalization, he suffered another embolic stroke in the right frontal lobe. By this time, the patient had completed a full course of antibiotics for infective endocarditis, and additional antibiotics were deemed unnecessary by our infectious disease specialists. Literature review highlighted that residual vegetations carry a higher risk for stroke, but no clear guidelines were found on how to intervene or assess the risk of hemorrhage with anticoagulation in this population. Consequently, a decision was made to initiate anticoagulation, Follow-up imaging revealed no evidence of hemorrhagic transformation. Subsequently, the patient remained stable and was discharged to a rehabilitation center, where he did not experience any further events.

Noncontrast Computed Tomography vs Computed Tomography Perfusion or Magnetic Resonance Imaging Selection in Late Presentation of Stroke With Large-Vessel Occlusion.

Importance: Advanced imaging for patient selection in mechanical thrombectomy is not widely available. Objective: To compare the clinical outcomes of patients selected for mechanical thrombectomy by noncontrast computed tomography (CT) vs those selected by computed tomography perfusion (CTP) or magnetic resonance imaging (MRI) in the extended time window. Design, Setting, and Participants: This multinational cohort study included consecutive patients with proximal anterior circulation occlusion stroke presenting within 6 to 24 hours of time last seen well from January 2014 to December 2020. This study was conducted at 15 sites across 5 countries in Europe and North America. The duration of follow-up was 90 days from stroke onset. Exposures: Computed tomography with Alberta Stroke Program Early CT Score, CTP, or MRI. Main Outcomes and Measures: The primary end point was the distribution of modified Rankin Scale (mRS) scores at 90 days (ordinal shift). Secondary outcomes included the rates of 90-day functional independence (mRS scores of 0-2), symptomatic intracranial hemorrhage, and 90-day mortality. Results: Of 2304 patients screened for eligibility, 1604 patients were included, with a median (IQR) age of 70 (59-80) years; 848 (52.9%) were women. A total of 534 patients were selected to undergo mechanical thrombectomy by CT, 752 by CTP, and 318 by MRI. After adjustment of confounders, there was no difference in 90-day ordinal mRS shift between patients selected by CT vs CTP (adjusted odds ratio [aOR], 0.95 [95% CI, 0.77-1.17]; P = .64) or CT vs MRI (aOR, 0.95 [95% CI, 0.8-1.13]; P = .55). The rates of 90-day functional independence (mRS scores 0-2 vs 3-6) were similar between patients selected by CT vs CTP (aOR, 0.90 [95% CI, 0.7-1.16]; P = .42) but lower in patients selected by MRI than CT (aOR, 0.79 [95% CI, 0.64-0.98]; P = .03). Successful reperfusion was more common in the CT and CTP groups compared with the MRI group (474 [88.9%] and 670 [89.5%] vs 250 [78.9%]; P < .001). No significant differences in symptomatic intracranial hemorrhage (CT, 42 [8.1%]; CTP, 43 [5.8%]; MRI, 15 [4.7%]; P = .11) or 90-day mortality (CT, 125 [23.4%]; CTP, 159 [21.1%]; MRI, 62 [19.5%]; P = .38) were observed. Conclusions and Relevance: In patients undergoing proximal anterior circulation mechanical thrombectomy in the extended time window, there were no significant differences in the clinical outcomes of patients selected with noncontrast CT compared with those selected with CTP or MRI. These findings have the potential to widen the indication for treating patients in the extended window using a simpler and more widespread noncontrast CT-only paradigm.

First off Label Endovascular Clinical Experience to Treat Diffuse Cerebral Venous Sinus Thrombosis Using the INARI FlowTriever System: Case Report.

Anticoagulation with heparin is the current mainstay treatment for Cerebral Venous Sinus Thrombosis (CVST). Endovascular treatment is increasingly being used to treat patients with CVST who are non-responsive to anticoagulation. These more aggressive interventions include catheter-based local chemical thrombolysis, balloon angioplasty and mechanical thrombectomy with uncertain safety and efficacy. Here we describe the first reported clinical experience using the INARI FlowTriever system to treat a patient presented with focal weakness and found to have diffuse CVST.