Racial/Ethnic Disparities in Acute Ischemic Stroke Treatment Within a Telestroke Network.

Background: The growth of telestroke services expanded the reach of acute stroke treatment. However, ethnic disparities in receiving such treatment have not been fully assessed. Materials and Methods: We reviewed prospectively maintained data on patients evaluated through the Medical University of South Carolina telestroke program between January 2016 and November 2018. Outcomes included odds of receiving intravenous recombinant tissue plasminogen activator (tPA), receiving mechanical thrombectomy (MT), and achieving door-to-needle (DTN) time ≤60 and ≤45 min among patients receiving tPA. We used logistic regression to analyze the contribution of race/ethnicity. Results: We included 2,977 patients, of whom 1,093 (36.7%) identified as nonwhite; of these, 1,048 patients (95.9%) identified as black or African American. Significantly more nonwhite patients were seen at a primary stroke center (PSC) (68.4% vs. 52.3% in whites, p < 0.001). However, white patients had significantly higher odds of receiving tPA (odds ratio [OR] 1.47, confidence interval [95% CI] 1.17-1.84). There was no significant difference in receiving MT between races. Among patients receiving tPA, whites had higher odds of DTN ≤45 min (OR 1.76, 1.20-2.57) and ≤60 min (OR 1.87, 95% CI 1.31-2.66). Conclusions: White patients had better odds achieving DTN ≤45 min and DTN ≤60 min if receiving tPA within a telestroke setting, as well as higher odds of receiving tPA, even after adjustment for comorbidities. This was noted despite white patients having less access to PSCs. However, larger scale studies are needed to further study the impact of ethnic disparities.

The Relationship Between Admission Systolic Blood Pressure and Mortality in Telestroke Patients.

Background: A "U-shaped" relationship between admission blood pressure (BP) and mortality (wherein patients within a middle range have better outcomes than patients at higher or lower extremes) in patients receiving intravenous recombinant tissue-plasminogen activator (tPA) has been previously described. We aim to determine if this U-shaped relationship persists for patients in a telestroke setting regardless of tPA administration. Materials and Methods: We conducted a retrospective chart review of the prospectively collected registry data for all patients seen through the Medical University of South Carolina (MUSC) telestroke network. Admission systolic BP (SBP) was divided into quartiles with thresholds based on the 25th, 50th, and 75th percentiles as cut points separately by tPA status. The primary outcomes of this study were odds of 90-day modified Rankin scale ≤2 and 90-day mortality. Logistic regression analyses were used to analyze associations between BP quartiles and these outcomes, adjusted for relevant clinical covariates. Results: Our sample comprised 1,232 patients evaluated for telestroke, 616 of whom received tPA. Patients in the second (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.15-0.77 in the tPA group, OR 0.27, 95% CI 01.0-0.78 in the non-tPA group) and third (OR 0.26, 95% CI 0.11-0.64 in the tPA group, OR 0.36, 95% CI 0.14-0.92 in the non-tPA group) quartiles of admission SBP had lower adjusted odds of 90-day mortality. Conclusions: Our findings support a U-shaped relationship between admission SBP and 90-day mortality in acute stroke patients regardless of tPA administration, after adjustment for relevant covariates. Further research into interventions regarding BP management poststroke is warranted.

Functional Outcomes of Intravenous Thrombolysis in Octogenarians and Nonagenarians Through Telestroke: Single-Center Experience.

Background: Patients aged ≥80 years are often underrepresented in stroke trials. Observational studies have shown that older patients have worse outcomes compared with younger patients, but outcomes in patients aged ≥80 years treated with intravenous (IV)-alteplase specifically through telestroke (TS) have not been studied. Aim: To compare clinical and safety outcomes in stroke patients aged ≥80 and 60-79 years treated with IV-alteplase via TS. Methods: The Medical University of South Carolina TS database was analyzed to identify IV-alteplase-treated patients aged 60-79 and ≥80 years between January 2015 and March 2018. Baseline demographics and TS-specific variables were compared. Clinical outcomes were assessed using the 90-day modified Rankin Scale (mRS). Safety outcomes were evaluated by comparing symptomatic intracranial hemorrhage (sICH). Multivariate logistic regression analysis was performed to determine odds ratio (OR) for good outcome (mRS 0-2) in the older age group at 90 days. Results: IV-alteplase was used in 151 patients in ≥80 years age group and 273 patients in 60-79 years age group. The older age group had more women and a higher National Institutes of Health Stroke Scale. The mean "ED-door-to-TS-consultant-login" time was shorter (21.6 min vs. 25.6 min; p = 0.048), but "TS-consultant-login-to-alteplase" time was longer (22.1 min vs. 19.3 min; p = 0.01) in the older age group. No difference was noted in eventual "door-to-needle" time. The older age group had fewer good outcomes (39.1% vs. 74%; p = 0.001) and more deaths (38% vs. 14%; p = 0.001) at 90 days. The sICH rates were similar in the two groups. The OR for good outcome in ≥80 years age group was 0.20 (95% CI: 0.12-0.34) after controlling for baseline variables. Conclusions: Stroke patients aged ≥80 years treated via TS have similar post-thrombolysis hemorrhage rates but worse clinical outcomes compared with patients aged 60-79 years.

Teleneurology Network to Improve Access to Neurologists for Patients in Rural Areas: A Real-World Experience.

Background: The need for neurologists has been steadily increasing over the past few years. The implementation of teleneurology networks could serve as a potential solution to this need. Methods: A retrospective review of the Medical University of South Carolina (MUSC) Teleneurology records for all consults performed between August 2014 and July 2018 was conducted. Collected data included number of consults, baseline characteristics, final diagnosis, and number of providers and hospitals over the study period. Results: A total of 4,542 Teleneurology consults were performed during the study period. The most common diagnosis was cerebrovascular disease, followed by seizure disorders. The number of consults per month increased throughout the study period from three in August 2014 to 257 in July 2018. The number of community hospitals covered has increased from 3 hospitals in August 2014 to 14 hospitals throughout the state of South Carolina in July 2018. Conclusion: Over 4 years, the MUSC teleneurology program has evolved into a robust partnership with 14 partner hospitals, and is now delivering more than 250 expert neurology consultations monthly to patients throughout the state of South Carolina.

Brain microvascular endothelial cells exhibit lower activation of the alternative complement pathway than glomerular microvascular endothelial cells.

Atypical hemolytic uremic syndrome (aHUS) and bone marrow transplantation-associated thrombotic microangiopathy (TA-TMA) are associated with excessive activation of the alternative complement pathway (AP) and with severe renal, but rarely cerebral, microvascular damage. Here, we compared AP activation and regulation in human glomerular and brain microvascular endothelial cells (GMVECs and BMVECs, respectively) unstimulated or stimulated by the proinflammatory cytokine, tumor necrosis factor (TNF). Compared with GMVECs and under both experimental conditions, BMVECs had increased gene expression of the AP-related genes C3, CFB, and C5 and decreased expression of CFD This was associated with increased expression in BMVECs (relative to GMVECs) of the genes for surface and soluble regulatory molecules (CD46, THBD, CD55, CFI, and CFH) suppressing formation of the AP C3 and C5 convertases. Of note, unlike GMVECs, BMVECs generated extremely low levels of C3a and C5a and displayed decreased activation of the AP (as measured by a lower percentage of Ba generation than GMVECs). Moreover, BMVECs exhibited increased function of CD141, mediating activation of the natural anticoagulant protein C, compared with GMVECs. We also found that the C3a receptor (C3aR) is present on both cell types and that TNF greatly increases C3AR1 expression in GMVECs, but only slightly in BMVECs. Higher AP activation and C3a generation in GMVECs than in BMVECs, coupled with an increase in C3aR production in TNF-stimulated GMVECs, provides a possible explanation for the predominance of renal damage, and the absence of cerebral injury, in individuals with episodes of aHUS and TA-TMA.

Long-Term Functional Outcome of Telestroke Patients Treated Under Drip-and-Stay Paradigm Compared with Patients Treated in a Comprehensive Stroke Center: A Single Center Experience.

Objective:The purpose of this study is to compare long-term functional outcome for patients who receive intravenous alteplase (tPA) at a primary stroke center (spoke) through telestroke consultations and remain at the spoke (drip-and-stay) with that for patients who receive tPA at the comprehensive stroke center (hub).Methods:Data on baseline characteristics, stroke severity on presentation, door to needle (DTN) time, the rate of symptomatic intracerebral hemorrhage (sICH) and long-term outcomes for all patients evaluated at the Medical University of South Carolina (MUSC) hub and MUSC telestroke network spoke sites between January 2016 and March 2017 were collected. Eligible patients received tPA at either the spoke or hub location during the study period. Patients who received mechanical thrombectomy were excluded from the study. Functional outcome was assessed with 90-day modified Rankin Scale (mRS). Descriptive statistics were used to compare patient demographics and clinical outcomes across the two groups.Results:Total of 426 were identified (60 hub patients and 366 drip-and-stay patients). There were no significant differences in patient age, sex, admission National Institute of Health Stroke Scale (NIHSS), sICH, or DTN times between the two groups. mRS of 0-2 at 90 days was achieved in 37 (61.7%) of the hub and in 255 (69.7%) in the drip-and-stay patients (p = 0.216). On regression analysis, there was no difference in the adjusted relative risk of having a lower mRS between drip-and-stay and hub patients (incidence rate ratio 1.14, p = 0.278, 95% confidence interval [0.9-1.43]).Conclusion:Our study shows no difference in the long-term functional outcome for patients who received tPA through telestroke consultation and remained at spoke hospitals (drip-and-stay) compared with patients who received tPA at the hub.

Shaping functional gut microbiota using dietary bioactives to reduce colon cancer risk.

Colon cancer is a multifactorial disease associated with a variety of lifestyle factors. Alterations in the gut microbiota and the intestinal metabolome are noted during colon carcinogenesis, implicating them as critical contributors or results of the disease process. Diet is a known determinant of health, and as a modifier of the gut microbiota and its metabolism, a critical element in maintenance of intestinal health. This review summarizes recent evidence demonstrating the role and responses of the intestinal microbiota during colon tumorigenesis and the ability of dietary bioactive compounds and probiotics to impact colon health from the intestinal lumen to the epithelium and systemically. We first describe changes to the intestinal microbiome, metabolome, and epithelium associated with colon carcinogenesis. This is followed by a discussion of recent evidence indicating how specific classes of dietary bioactives, prebiotics, or probiotics affect colon carcinogenesis. Lastly, we briefly address the prospects of using multiple 'omics' techniques to integrate the effects of diet, host, and microbiota on colon tumorigenesis with the goal of more fully appreciating the interconnectedness of these systems and thus, how these approaches can be used to advance personalized nutrition strategies and nutrition research.

Optimization of novel monobactams with activity against carbapenem-resistant Enterobacteriaceae - Identification of LYS228.

Metallo-ß-lactamases (MBLs), such as New Delhi metallo-ß-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative bacteria to all classes of ß-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobactam drugs like aztreonam have limited clinical utility against MBL-expressing strains because they are impacted by serine ß-lactamases (SBLs), which are often co-expressed in clinical isolates. Here, we optimized novel monobactams for stability against SBLs, which led to the identification of LYS228 (compound 31). LYS228 is potent in the presence of all classes of ß-lactamases and shows potent activity against carbapenem-resistant isolates of Enterobacteriaceae (CRE).

TNF Regulates Essential Alternative Complement Pathway Components and Impairs Activation of Protein C in Human Glomerular Endothelial Cells.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy with severe renal injury secondary to an overactive alternative complement pathway (AP). aHUS episodes are often initiated or recur during inflammation. We investigated gene expression of the surface complement regulatory proteins (CD55, CD59, CD46, and CD141 [thrombomodulin]) and AP components in human glomerular microvascular endothelial cells (GMVECs) and in HUVECs, a frequently used investigational model of endothelial cells. Surface complement regulatory proteins were also quantified by flow cytometry. All experiments were done with and without exposure to IL-1ß or TNF. Without cytokine stimulation, we found that GMVECs had greater AP activation than did HUVECs. With TNF stimulation, THBD gene expression and corresponding CD141 surface presence in HUVECs and GMVECs were reduced, and gene expression of complement components C3 (C3) and factor B (CFB) was increased. Consequently, AP activation, measured by Ba production, was increased, and conversion of protein C (PC) to activated PC by CD141-bound thrombin was decreased, in GMVECs and HUVECs exposed to TNF. IL-1ß had similar, albeit lesser, effects on HUVEC gene expression, and it only slightly affected GMVEC gene expression. To our knowledge, this is the first detailed study of the expression/display of AP components and surface regulatory proteins in GMVECs with and without cytokine stimulation. In aHUS patients with an underlying overactive AP, additional stimulation of the AP and inhibition of activated PC-mediated anticoagulation in GMVECs by the inflammatory cytokine TNF are likely to provoke episodes of renal failure.

Door to Needle Time over Telestroke-A Comprehensive Stroke Center Experience.

BACKGROUND: The implementation of telestroke programs has allowed patients living in rural areas suffering from acute ischemic stroke to receive expert acute stroke consultation and intravenous Alteplase (tPA). The purpose of this study is to compare door to needle (DTN) time when tPA is administered at telestroke sites (spokes) through telestroke consultations compared to tPA administration at the comprehensive stroke center (hub). METHODS: Data on all patients who received intravenous tPA at the hub and spoke hospitals through a large telestroke program between May 2008 and December 2016 were collected. Baseline characteristics were compared between the two groups, and the percentage of patients meeting DTN guidelines was compared between the hub and spoke hospitals during the study period. Comparison of DTN before and after the implementation of a quality improvement project was performed. RESULTS: A total of 1,665 patients received tPA at either the spoke (n = 1,323) or the hub (n = 342) during the study period. Baseline characteristics were comparable in both treatment groups. Before the intervention, DTN time <60 min was achieved in 88% of the hub patients versus 38% of the spoke patients. This difference between the two groups decreased by 35 percentage points, controlling for year (p = 0.0018) after the interventions. CONCLUSION: Overall, DTN is longer at the spoke hospitals compared to the hub hospital. This can be improved by various interventions that target quality, training, education, and improving the comfort level of the staff at partner hospitals when treating acute stroke patients.

Rate of Symptomatic Intracerebral Hemorrhage Related to Intravenous tPA Administered Over Telestroke Within 4.5-Hour Window.

BACKGROUND: Intravenous tissue plasminogen activator (tPA) remains the cornerstone medical treatment for acute ischemic stroke. The establishment of telestroke technology has allowed patients presenting to hospitals that lack expert stroke care to be evaluated and receive tPA. The safety of tPA administered through telestroke has been evaluated only when tPA is given within the 3-h window of last known normal. The purpose of this study is to evaluate the safety of tPA when administered through telestroke within a 4.5-h window. METHODS: A retrospective analysis on the prospectively collected database for all patients who received tPA at the Medical University of South Carolina Comprehensive Stroke Center (MUSC) (hub), as well as the MUSC telestroke network partner hospitals (spokes), was performed. Collected data included demographics, baseline characteristics, time from last known well to tPA administration, and symptomatic intracerebral hemorrhage (sICH) rates. Logistic regression was used to examine the odds of a sICH in patients at spoke sites compared with the hub controlling for patient stroke severity, gender, age, and race. RESULTS: A total of 830 patients were identified. Median National Institute of Health Stroke Scale was significantly higher among patients treated at the hub (9 vs. 8, p = 0.013), and the hub treated a higher percentage of nonwhite patients (p = 0.039). sICH occurred in 27 (4.8%) in the spoke group and 10 (3.8%) in the hub group (p = 0.523). Logistic regression results found no significant difference in the odds of sICH if tPA is given in a spoke site. CONCLUSIONS: Our study shows similar rates of sICH when intravenous tPA is administered at spokes through telestroke network compared with the hub.

Homeostatic responses of colonic LGR5+ stem cells following acute in vivo exposure to a genotoxic carcinogen.

Perturbations in DNA damage, DNA repair, apoptosis and cell proliferation in the base of the crypt where stem cells reside are associated with colorectal cancer (CRC) initiation and progression. Although the transformation of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)(+) cells is an extremely efficient route towards initiating small intestinal adenomas, the role of Lgr5(+) cells in CRC pathogenesis has not been well investigated. Therefore, we further characterized the properties of colonic Lgr5(+) cells compared to differentiated cells in Lgr5-EGFP-IRES-creER(T2) knock-in mice at the initiation stage of carcinogen azoxymethane (AOM)-induced tumorigenesis using a quantitative immunofluorescence microscopy approach. At 12 and 24h post-AOM treatment, colonic Lgr5(+) stem cells (GFP(high)) were preferentially damaged by carcinogen, exhibiting a 4.7-fold induction of apoptosis compared to differentiated (GFP(neg)) cells. Furthermore, with respect to DNA repair, O(6)-methylguanine DNA methyltransferase (MGMT) expression was preferentially induced (by 18.5-fold) in GFP(high) cells at 24h post-AOM treatment compared to GFP(neg) differentiated cells. This corresponded with a 4.3-fold increase in cell proliferation in GFP(high) cells. These data suggest that Lgr5(+) stem cells uniquely respond to alkylation-induced DNA damage by upregulating DNA damage repair, apoptosis and cell proliferation compared to differentiated cells in order to maintain genomic integrity. These findings highlight the mechanisms by which colonic Lgr5(+) stem cells respond to cancer-causing environmental factors.

Increased dietary iron and radiation in rats promote oxidative stress, induce localized and systemic immune system responses, and alter colon mucosal environment.

Astronauts are exposed to increased body iron stores and radiation, both of which can cause oxidative damage leading to negative health effects. The purpose of this study was to investigate combined effects of high dietary iron (650 mg/kg diet) and radiation exposure (0.375 Gy cesium-137 every other day for 16 d) on markers of oxidative stress, immune system function, and colon mucosal environment in male Sprague-Dawley rats (n=8/group). Control rats consumed adequate iron (45 mg/kg diet) and were not irradiated. Combined treatments increased liver glutathione peroxidase, serum catalase, and colon myeloperoxidase while decreasing total fecal short-chain fatty acid concentrations. The high-iron diet alone increased leukocyte count. Radiation decreased the T-cell CD4:CD8 ratio. Plasma iron was negatively correlated with cytokine production in activated monocytes. Genes involved in colon microbial signaling, immune response, and injury repair were altered by radiation. Genes involved with injury repair and pathogen recognition changed with dietary iron. These data demonstrate that dietary iron and radiation, alone and combined, contribute to oxidative stress that is related to immune system alterations in circulation and the colon. The model presented may help us better understand the changes to these systems that have been identified among astronauts.

Interaction of Shiga toxin with the A-domains and multimers of von Willebrand Factor.

Shiga toxin (Stx) produced by enterohemorrhagic Escherichia coli causes diarrhea-associated hemolytic-uremic syndrome (DHUS), a severe renal thrombotic microangiopathy. We investigated the interaction between Stx and von Willebrand Factor (VWF), a multimeric plasma glycoprotein that mediates platelet adhesion, activation, and aggregation. Stx bound to ultra-large VWF (ULVWF) secreted from and anchored to stimulated human umbilical vein endothelial cells, as well as to immobilized VWF-rich human umbilical vein endothelial cell supernatant. This Stx binding was localized to the A1 and A2 domain of VWF monomeric subunits and reduced the rate of ADAMTS-13-mediated cleavage of the Tyr(1605)-Met(1606) peptide bond in the A2 domain. Stx-VWF interaction and the associated delay in ADAMTS-13-mediated cleavage of VWF may contribute to the pathophysiology of DHUS.

Thrombotic microangiopathies and the linkage between von Willebrand factor and the alternative complement pathway.

Molecular linkages between von Willebrand factor (VWF) and the alternative complement pathway (AP) have recently been discovered. Endothelial cell (EC)-anchored ultra-large (UL) VWF multimeric strings function as an activating surface for the AP. C3 (in active C3b form) binds to the EC-anchored ULVWF strings, and promotes the assembly of C3bBb (C3 convertase) and C3bBbC3b (C5 convertase). These linkages may help to explain enigmatic clinical problems related to thrombotic microangiopathies, including some cases of refractory thrombotic thrombocytopenic purpura (TTP), TTP associated with only mild-modest deficiencies of ADAMTS-13, the provocation (or exacerbation) of acute episodes in patients with the atypical hemolytic uremic syndrome, and thrombosis in paroxysmal nocturnal hemoglobinuria. Recent experiments have also demonstrated that complement factor H performs a dual role: participating in regulation of the AP by binding to EC-anchored ULVWF strings; and functioning as a reductase to decrease the size of soluble VWF multimers.

The global relevance of locally grounded ethnobiology.

While ethnobiology is a discipline that focuses on the local, it has an outstanding, but not yet fully realized potential to address global issues. Part of this unrealized potential is that universalistic approaches often do not fully recognize culturally grounded perspectives and there are multiple challenges with scaling up place-based research. However, scalability is paramount to ensure that the intimate and context-specific diversity of human-environmental relationships and understandings are recognized in global-scale planning and policy development. Here, we identify four pathways to enable the scalability of place-based ethnobiological research from the ground up: local-to-global dialogues, aggregation of published data, multi-sited studies, and geospatial analyses. We also discuss some major challenges and consideration to encourage continuous reflexivity in these endeavours and to ensure that scalability does not contribute to unnecessarily decontextualizing, co-opting, or overwriting the epistemologies of Indigenous Peoples and local communities. As ethnobiology navigates multiple scales of time and space and seeks to increase its breadth, this study shows that the use of deliberately global approaches, when carefully nested within rich field-based and ecological and ethnographically grounded data, can contribute to: (1) upscaling case-specific insights to unveil global patterns and dynamics in the biocultural contexts of Indigenous Peoples and local communities; (2) bringing ethnobiological knowledge into resolutions that can influence global environmental research and policy agendas; and (3) enriching ethnobiology's field-based ethos with a deliberate global analytical focus.

Mechanical activation of a multimeric adhesive protein through domain conformational change.

The mechanical force-induced activation of the adhesive protein von Willebrand factor (VWF), which experiences high hydrodynamic forces, is essential in initiating platelet adhesion. The importance of the mechanical force-induced functional change is manifested in the multimeric VWF's crucial role in blood coagulation, when high fluid shear stress activates plasma VWF (PVWF) multimers to bind platelets. Here, we showed that a pathological level of high shear stress exposure of PVWF multimers results in domain conformational changes, and the subsequent shifts in the unfolding force allow us to use force as a marker to track the dynamic states of the multimeric VWF. We found that shear-activated PVWF multimers are more resistant to mechanical unfolding than nonsheared PVWF multimers, as indicated in the higher peak unfolding force. These results provide insight into the mechanism of shear-induced activation of PVWF multimers.