Trastuzumab and first-line taxane chemotherapy in metastatic breast cancer patients with a HER2-negative tumor and HER2-positive circulating tumor cells: a phase II trial.

PURPOSE: HER2 overexpressing circulating tumor cells (CTCs) are observed in up to 25% of HER2-negative metastatic breast cancer patients. Since targeted anti-HER2 therapy has drastically improved clinical outcomes of patients with HER2-positive breast cancer, we hypothesized that patients with HER2 overexpressing CTCs might benefit from the addition of trastuzumab to chemotherapy. METHODS: In this single-arm, phase II trial, patients with HER2-positive CTCs received trastuzumab as addition to first-line treatment with taxane chemotherapy. Patients with detectable CTCs but without HER2 overexpression that received taxane chemotherapy only, were used as control group. The primary outcome measure was progression-free rate at 6 months (PFR6), with a target of 80%. In November 2022, the study was terminated early due to slow patient accrual. RESULTS: 63 patients were screened, of which eight patients had HER2-positive CTCs and were treated with trastuzumab. The median number of CTCs was 15 per 7.5 ml of blood (range 1-131) in patients with HER2-positive CTCs, compared to median 5 (range 1-1047) in the control group. PFR6 was 50% in the trastuzumab group and 54% in the taxane monotherapy group, with no significant difference in median PFS (8 versus 9 months, p = 0.51). CONCLUSION: No clinical benefit of trastuzumab was observed, although this study was performed in a limited number of patients. Additionally, we observed a strong correlation between the number of evaluable CTCs and the presence of HER2-positive CTCs. We argue that randomized studies investigating agents that are proven to be solely effective in the HER2-positive patient group in patients with HER2-positive CTCs and HER2-negative tissue are currently infeasible. Several factors contribute to this impracticality, including the need for more stringent thresholds, and the rapidly evolving landscape of cancer treatments.

Effectiveness of pulmonary valve-sparing strategy for transatrial-transpulmonary repair of tetralogy of Fallot: a single institution experience.

OBJECTIVE: We report the midterm results of our strategy utilizing transatrial-transpulmonary repair for tetralogy of Fallot at a single institution in a low-middle income country. METHODS: Medical records were retrospectively reviewed for 532 consecutive patients who underwent definitive repair of tetralogy of Fallot at our institution from 2010 to 2020. RESULTS: The median age and weight of patients in the study patients were 11.6 months (interquartile range, 8.6-17.2 months) and 7.5 kg (interquartile range, 6.8-8.8 kg). The pulmonary valve annulus was preserved (no transannular patch) in 398 patients (75%) and a mini-transannular patch was utilized for 134 patients (25%). The overall survival was 98% at 1 year, and 97% at 10-years follow-up, respectively. Longer postoperative ventilation time was the only risk factor correlated to early death (p = 0.004; Odds Risk, 1.04; 95% confidence intervals, 1.01-1.07). Fourteen patients required pulmonary valve replacement (2.6%, 14/532), four required surgical resection to relieve right ventricular outflow tract obstruction (0.8%, 4/532), and freedom from reoperation of the right ventricular outflow tract was 87% at 10 years. The only risk factor for right ventricular outflow tract reoperation was a postoperative systolic pressure gradient through the right ventricular outflow tract of greater than 50 mmHg (p < 0.001; HR, 47; 95% confidence intervals, 9.1-244). In total, 94.6% (471/489) of the patients were asymptomatic at the latest follow-up without significant arrhythmia. CONCLUSION: At our institution in an low-middle income country, the transatrial-transpulmonary repair for tetralogy of Fallot has excellent midterm results with few reoperations required. Close long-term follow-up is essential for patients who undergo repair with a mini-transannular patch and may eventually require pulmonary valve replacement.

Adverse childhood experiences and early initiation of substance use: A survival analysis.

OBJECTIVE: Early adversity, such as adverse childhood experiences (ACEs), is a risk factor for the development of substance use disorder (SUD). ACEs are associated with earlier initiation of substance use. This study examined the relationship between ACEs and age of initiation of substance use using survival analysis. It is hypothesized that individuals with higher ACEs will have an earlier age of initiation. METHOD: Participants were recruited from the University of Kentucky's Laboratory for Human Behavioral Pharmacology. Participants were 18 years or older, English speaking, and actively engaged in substance use. Participants were not in substance abuse treatment nor were they seeking treatment. ACE scores were calculated, and age of substance use initiation was recorded. A Cox proportional hazard model was used to examine the effect of ACE score on age of substance use initiation. RESULTS: A total of 107 participants completed the study. An average number of 2.3 ACEs (SD = 2.2) were endorsed with 24% of participants reporting 4 or more ACEs. Higher ACE scores were associated with cigarette smoking and non-medical prescription opioid use onset ( hazard ratio (HR) = 1.14, 95% CI=1.02-1.28, p = 0.02, and HR=1.19, 95% CI = 1.04-1.37, p = 0.01, respectively. CONCLUSIONS: A significant association was found between higher ACE scores and earlier initiation of cigarette and non-medical prescription opioid use, consistent with prior research. Primary prevention of ACEs, screening for ACEs during childhood, and interventions for ACEs if detected, may help to reduce the risk of substance use/SUD in adulthood.

Comparative safety of tenecteplase vs alteplase for acute ischemic stroke.

INTRODUCTION: Tenecteplase has been compared to alteplase in acute stroke randomized trials, with similar outcomes and safety measures, but higher doses of tenecteplase have been associated with higher hemorrhage rates in some studies. Limited data are available on the safety of tenecteplase outside of clinical trials. METHODS: We examined the safety measures of intracranial hemorrhage, angioedema, and serious extracranial adverse events in a 21-hospital integrated healthcare system that switched from alteplase (0.9 mg/kg, maximum dose 90 mg) to tenecteplase (0.25 mg/kg, maximum dose 25 mg) for acute ischemic stroke. RESULTS: Among 3,689 subjects, no significant differences were seen between tenecteplase and alteplase in the rate of intracranial hemorrhage (ICH), parenchymal hemorrhage, or volume of parenchymal hemorrhage. Symptomatic hemorrhage (sICH) was not different between the two agents: sICH by NINDS criteria was 2.0 % for alteplase vs 2.3 % for tenecteplase (P = 0.57), and sICH by SITS criteria was 0.8 % vs 1.1 % (P = 0.39). Adjusted logistic regression models also showed no differences between tenecteplase and alteplase: the odds ratio for tenecteplase (vs alteplase) modeling sICH by NINDS criteria was 0.9 (95 % CI 0.33 - 2.46, P = 0.83) and the odds ratio for tenecteplase modeling sICH by SITS criteria was 1.12 (95 % CI 0.25 - 5.07, P = 0.89). Rates of angioedema and serious extracranial adverse events were low and did not differ between tenecteplase and alteplase. Elapsed door-to-needle times showed a small improvement after the switch to tenecteplase (51.8 % treated in under 30 min with tenecteplase vs 43.5 % with alteplase, P < 0.001). CONCLUSION: In use outside of clinical trials, complication rates are similar between tenecteplase and alteplase. In the context of a stroke telemedicine program, the rates of hemorrhage observed with either agent were lower than expected based on prior trials and registry data. The more easily prepared tenecteplase was associated with a lower door-to-needle time.

A comparative effectiveness study of carotid intervention for long-term stroke prevention in patients with severe asymptomatic stenosis from a large integrated health system.

OBJECTIVE: The results of current prospective trials comparing the effectiveness of carotid endarterectomy (CEA) vs standard medical therapy for long-term stroke prevention in patients with asymptomatic carotid stenosis (ACS) will not be available for several years. In this study, we compared the observed effectiveness of CEA and standard medical therapy vs standard medical therapy alone to prevent ipsilateral stroke in a contemporary cohort of patients with ACS. METHODS: This cohort study was conducted in a large integrated health system in adult subjects with 70% to 99% ACS (no neurologic symptom within 6 months) with no prior ipsilateral carotid artery intervention. Causal inference methods were used to emulate a conceptual randomized trial using data from January 1, 2008, through December 31, 2017, for comparing the event-free survival over 96 months between two treatment strategies: (1) CEA within 12 months from cohort entry vs (2) no CEA (standard medical therapy alone). To account for both baseline and time-dependent confounding, inverse probability weighting estimation was used to derive adjusted hazard ratios, and cumulative risk differences were assessed based on two logistic marginal structural models for counterfactual hazards. Propensity scores were data-adaptively estimated using super learning. The primary outcome was ipsilateral anterior ischemic stroke. RESULTS: The cohort included 3824 eligible patients with ACS (mean age: 73.7 years, 57.9% male, 12.3% active smokers), of whom 1467 underwent CEA in the first year, whereas 2297 never underwent CEA. The median follow-up was 68 months. A total of 1760 participants (46%) died, 445 (12%) were lost to follow-up, and 158 (4%) experienced ipsilateral stroke. The cumulative risk differences for each year of follow-up showed a protective effect of CEA starting in year 2 (risk difference = 1.1%, 95% confidence interval: 0.5%-1.6%) and persisting to year 8 (2.6%, 95% confidence interval: 0.3%-4.8%) compared with patients not receiving CEA. CONCLUSIONS: In this contemporary cohort study of patients with ACS using rigorous analytic methodology, CEA appears to have a small but statistically significant effect on stroke prevention out to 8 years. Further study is needed to appropriately select the subset of patients most likely to benefit from intervention.

Optic neuropathy after COVID-19 vaccination: a report of two cases.

PURPOSE: We report two cases of optic nerve pathology after the administration of the Pfizer-BioNTech and AstraZeneca-Oxford COVID-19 vaccines, respectively, and describe the implications for management of post-vaccination central nervous system (CNS) inflammation. CASE REPORTS: A 69-year-old woman presented with bilateral optic nerve head oedema, 16 days after the second dose of the Pfizer-BioNTech vaccine. She was diagnosed with post-vaccination CNS inflammatory syndrome and was treated for five days with intravenous methylprednisolone at a dose of 1 gram per day. Her optic disc swelling improved, and her vision stabilised. A 32-year-old woman presented six days after her first dose of the AstraZeneca-Oxford vaccine with two days of sudden onset of progressive blurring of vision in her left eye. Posterior segment examination revealed left optic disc swelling, and an MRI of the brain, orbit, and cervical spine was significant for left optic nerve enhancement. The patient was diagnosed with a unilateral post-vaccination optic neuritis. She was treated with a three-day course of intravenous methylprednisolone followed by oral prednisone. Her optic disc swelling and visual field improved, and she recovered 6/6 vision. CONCLUSIONS: Clinicians and patients should be aware of the potential for post-vaccination CNS inflammatory syndromes associated with COVID-19 vaccine administration. Neuroimaging and cerebrospinal fluid analysis may aid in the diagnosis of the cause of vision loss. Further studies are needed to evaluate the spectrum and frequency of optic nerve involvement associated with COVID-19 vaccination.

Natural History of Asymptomatic Moderate Carotid Artery Stenosis in a Large Community-Based Cohort.

BACKGROUND: Moderate carotid artery stenosis is a poorly defined risk factor for ischemic stroke. As such, practice recommendations are lacking. In this study, we describe the long-term risk of stroke in patients with moderate asymptomatic stenosis in an integrated health care system. METHODS: All adult patients with asymptomatic moderate (50%-69%) internal carotid artery stenosis between 2008 and 2012 were identified, with follow-up through 2017. The primary outcome was acute ischemic stroke attributed to the ipsilateral carotid artery. Stroke rates were calculated using competing risk analysis. Secondary outcomes included disease progression, ipsilateral intervention, and long-term survival. RESULTS: Overall, 11 614 arteries with moderate stenosis in 9803 patients were identified. Mean age was 74.2±9.9 years with 51.4% women. Mean follow-up was 5.1±2.9 years. There were 180 ipsilateral ischemic strokes (1.6%) identified (crude annual risk, 0.31% [95% CI, 0.21%-0.41%]), of which thirty-one (17.2%) underwent subsequent intervention. Controlling for death and intervention as competing risks, the cumulative incidence of stroke was 1.2% (95% CI, 1.0%-1.4%) at 5 years and 2.0% (95% CI, 1.7%-2.4%) at 10 years. Of identified strokes, 50 (27.8%) arteries had progressed to severe stenosis or occlusion. During follow-up, there were 17 029 carotid studies performed in 5951 patients, revealing stenosis progression in 1674 (14.4%) arteries, including 1614 (13.9%) progressing to severe stenosis and 60 (0.5%) to occlusion. The mean time to stenosis progression was 2.6±2.1 years. Carotid intervention occurred in 708 arteries (6.1%). Of these, 66.1% (468/708) had progressed to severe stenosis. The overall mortality rate was 44.5%, with 10.5% of patients lost to follow-up. CONCLUSIONS: In this community-based sample of patients with asymptomatic moderate internal carotid artery stenosis followed for an average of 5 years, the cumulative incidence of stroke is low out to 10 years. Future research is needed to optimize management strategies for this population.

Incidence of Ischemic Stroke in Patients With Asymptomatic Severe Carotid Stenosis Without Surgical Intervention.

Importance: Optimal management of patients with asymptomatic severe carotid stenosis is uncertain, due to advances in medical care and a lack of contemporary data comparing medical and surgical treatment. Objective: To estimate stroke outcomes among patients with medically treated asymptomatic severe carotid stenosis who did not undergo surgical intervention. Design, Setting, and Participants: Retrospective cohort study that included 3737 adult participants with asymptomatic severe (70%-99%) carotid stenosis diagnosed between 2008 and 2012 and no prior intervention or ipsilateral neurologic event in the prior 6 months. Participants received follow-up through 2019, and all were members of an integrated US regional health system serving 4.5 million members. Exposures: Imaging diagnosis of asymptomatic carotid stenosis of 70% to 99%. Main Outcomes and Measures: Occurrence of ipsilateral carotid-related acute ischemic stroke. Censoring occurred with death, disenrollment, or ipsilateral intervention. Results: Among 94 822 patients with qualifying imaging studies, 4230 arteries in 3737 (mean age, 73.8 [SD 9.5 years]; 57.4% male) patients met selection criteria including 2539 arteries in 2314 patients who never received intervention. The mean follow-up in this cohort was 4.1 years (SD 3.6 years). Prior to any intervention, there were 133 ipsilateral strokes with a mean annual stroke rate of 0.9% (95% confidence interval [CI], 0.7%-1.2%). The Kaplan-Meier estimate of ipsilateral stroke by 5 years was 4.7% (95% CI, 3.9%-5.7%). Conclusions and Relevance: In a community-based cohort of patients with asymptomatic severe carotid stenosis who did not undergo surgical intervention, the estimated rate of ipsilateral carotid-related acute ischemic stroke was 4.7% over 5 years. These findings may inform decision-making regarding surgical and medical treatment for patients with asymptomatic severe carotid artery stenosis.

Vertebrate Animal Models of RP59: Current Status and Future Prospects.

Retinitis pigmentosa-59 (RP59) is a rare, recessive form of RP, caused by mutations in the gene encoding DHDDS (dehydrodolichyl diphosphate synthase). DHDDS forms a heterotetrameric complex with Nogo-B receptor (NgBR; gene NUS1) to form a cis-prenyltransferase (CPT) enzyme complex, which is required for the synthesis of dolichol, which in turn is required for protein N-glycosylation as well as other glycosylation reactions in eukaryotic cells. Herein, we review the published phenotypic characteristics of RP59 models extant, with an emphasis on their ocular phenotypes, based primarily upon knock-in of known RP59-associated DHDDS mutations as well as cell type- and tissue-specific knockout of DHDDS alleles in mice. We also briefly review findings in RP59 patients with retinal disease and other patients with DHDDS mutations causing epilepsy and other neurologic disease. We discuss these findings in the context of addressing "knowledge gaps" in our current understanding of the underlying pathobiology mechanism of RP59, as well as their potential utility for developing therapeutic interventions to block the onset or to dampen the severity or progression of RP59.

Establishing a carotid artery stenosis disease cohort for comparative effectiveness research using natural language processing.

OBJECTIVE: Investigation of asymptomatic carotid stenosis treatment is hindered by the lack of a contemporary population-based disease cohort. We describe the use of natural language processing (NLP) to identify stenosis in patients undergoing carotid imaging. METHODS: Adult patients with carotid imaging between 2008 and 2012 in a large integrated health care system were identified and followed through 2017. An NLP process was developed to characterize carotid stenosis according to the Society of Radiologists in Ultrasound (for ultrasounds) and North American Symptomatic Carotid Endarterectomy Trial (NASCET) (for axial imaging) guidelines. The resulting algorithm assessed text descriptors to categorize normal/non-hemodynamically significant stenosis, moderate or severe stenosis as well as occlusion in both carotid ultrasound (US) and axial imaging (computed tomography and magnetic resonance angiography [CTA/MRA]). For US reports, internal carotid artery systolic and diastolic velocities and velocity ratios were assessed and matched for laterality to supplement accuracy. To validate the NLP algorithm, positive predictive value (PPV or precision) and sensitivity (recall) were calculated from simple random samples from the population of all imaging studies. Lastly, all non-normal studies were manually reviewed for confirmation for prevalence estimates and disease cohort assembly. RESULTS: A total of 95,896 qualifying index studies (76,276 US and 19,620 CTA/MRA) were identified among 94,822 patients including 1059 patients who underwent multiple studies on the same day. For studies of normal/non-hemodynamically significant stenosis arteries, the NLP algorithm showed excellent performance with a PPV of 99% for US and 96.5% for CTA/MRA. PPV/sensitivity to identify a non-normal artery with correct laterality in the CTA/MRA and US samples were 76.9% (95% confidence interval [CI], 74.1%-79.5%)/93.1% (95% CI, 91.1%-94.8%) and 74.7% (95% CI, 69.3%-79.5%)/94% (95% CI, 90.2%-96.7%), respectively. Regarding cohort assembly, 15,522 patients were identified with diseased carotid artery, including 2674 exhibiting equal bilateral disease. This resulted in a laterality-specific cohort with 12,828 moderate, 5283 severe, and 1895 occluded arteries and 326 diseased arteries with unknown stenosis. During follow-up, 30.1% of these patients underwent 61,107 additional studies. CONCLUSIONS: Use of NLP to detect carotid stenosis or occlusion can result in accurate exclusion of normal/non-hemodynamically significant stenosis disease states with more moderate precision with lesion identification, which can substantially reduce the need for manual review. The resulting cohort allows for efficient research and holds promise for similar reporting in other vascular diseases.

Long-term stroke risk with carotid endarterectomy in patients with severe carotid stenosis.

OBJECTIVE: Informed debate regarding the optimal use of carotid endarterectomy (CEA) for stroke risk reduction requires contemporary assessment of both long-term risk and periprocedural risk. In this study, we report long-term stroke and death risk after CEA in a large integrated health care system. METHODS: All patients with documented severe (70%-99%) stenosis from 2008 to 2012 who underwent CEA were identified and stratified by asymptomatic or symptomatic indication. Those with prior ipsilateral interventions were excluded. Patients were followed up through 2017 for the primary outcomes of any stroke/death within 30 days of intervention and long-term ipsilateral ischemic stroke; secondary outcomes were any stroke and overall survival. RESULTS: Overall, 1949 patients (63.2% male; mean age, 71.3 ± 8.9 years) underwent 2078 primary CEAs, 1196 (58%) for asymptomatic stenosis and 882 (42%) for symptomatic stenosis. Mean follow-up was 5.5 ± 2.7 years. Median time to surgery was 72.0 (interquartile range, 38.5-198.0) days for asymptomatic patients and 21.0 (interquartile range, 5.0-55.0) days for symptomatic patients (P < .001). Most of the patients' demographics and characteristics were similar in both groups. Controlled blood pressure rates were similar at the time of CEA. Baseline statin use was seen in 60.5% of the asymptomatic group compared with 39.9% in the symptomatic group (P < .001), and statin adherence by 80% medication possession ratio was 19.3% asymptomatic vs 12.4% symptomatic (P < .001). The crude overall 30-day any stroke/death rates were 0.9% and 1.5% for the asymptomatic group and the symptomatic group, respectively. The 5-year risk of ipsilateral stroke and a combined end point of any stroke/death by Kaplan-Meier survival analysis were 2.5% and 28.7% for the asymptomatic group and 4.0% and 31.4% for the symptomatic group, respectively. Unadjusted cumulative all-cause survival was 74.2% for the asymptomatic group and 71.8% for the symptomatic group at 5 years. CONCLUSIONS: In a contemporary review of CEA, outcomes for either operative indication show low adverse events perioperatively and low long-term stroke risk up to 5 years. These results are well within consensus guidelines and published trial outcomes and should help inform the discussion around optimal CEA use for severe carotid stenosis.

Selective inhibition of Rhizopus eumelanin biosynthesis by novel natural product scaffold-based designs caused significant inhibition of fungal pathogenesis.

Melanin is a dark color pigment biosynthesized naturally in most living organisms. Fungal melanin is a major putative virulence factor of Mucorales fungi that allows intracellular persistence by inducing phagosome maturation arrest. Recently, it has been shown that the black pigments of Rhizopus delemar is of eumelanin type, that requires the involvement of tyrosinase (a copper-dependent enzyme) in its biosynthesis. Herein, we have developed a series of compounds (UOSC-1-14) to selectively target Rhizopus melanin and explored this mechanism therapeutically. The compounds were designed based on the scaffold of the natural product, cuminaldehyde, identified from plant sources and has been shown to develop non-selective inhibition of melanin production. While all synthesized compounds showed significant inhibition of Rhizopus melanin production and limited toxicity to mammalian cells, only four compounds (UOSC-1, 2, 13, and 14) were selected as promising candidates based on their selective inhibition to fungal melanin. The activity of compound UOSC-2 was comparable to the positive control kojic acid. The selected candidates showed significant inhibition of Rhizopus melanin but not human melanin by targeting the fungal tyrosinase, and with an IC50 that are 9 times lower than the reference standard, kojic acid. Furthermore, the produced white spores were phagocytized easily and cleared faster from the lungs of infected immunocompetent mice and from the human macrophages when compared with wild-type spores. Collectively, the results suggested that the newly designed derivatives, particularly UOSC-2 can serve as promising candidate to overcome persistence mechanisms of fungal melanin production and hence make them accessible to host defenses.

Oncology clinical trials nursing: A scoping review.

In the 21st century, cancer is a disease that captures much of our attention for its complexity, and its physical, emotional, and financial impacts on one's life. Research attention and investment in cancer management has made it the most studied disease in clinical trials globally. Clinical trials nurses are part of the oncology research team and a fundamental factor in trial success. Their direct relationship with research subjects is the key connection in the operation of clinical trials at the front line. The influx and complexity of oncology clinical trials has transformed both oncology nursing practice in general and led to the development of the unique subspecialty of the oncology clinical trials nurse. This scoping review investigated the role and future practice of the clinical trials nurse.

Interventions Targeting Racial/Ethnic Disparities in Stroke Prevention and Treatment.

Systemic racism is a public health crisis. Systemic racism and racial/ethnic injustice produce racial/ethnic disparities in health care and health. Substantial racial/ethnic disparities in stroke care and health exist and result predominantly from unequal treatment. This special report aims to summarize selected interventions to reduce racial/ethnic disparities in stroke prevention and treatment. It reviews the social determinants of health and the determinants of racial/ethnic disparities in care. It provides a focused summary of selected interventions aimed at reducing stroke risk factors, increasing awareness of stroke symptoms, and improving access to care for stroke because these interventions hold the promise of reducing racial/ethnic disparities in stroke death rates. It also discusses knowledge gaps and future directions.

Acute Stroke Presentation, Care, and Outcomes in Community Hospitals in Northern California During the COVID-19 Pandemic.

BACKGROUND AND PURPOSE: Shelter-in-place (SIP) orders implemented to mitigate severe acute respiratory syndrome coronavirus 2 spread may inadvertently discourage patient care-seeking behavior for critical conditions like acute ischemic stroke. We aimed to compare temporal trends in volume of acute stroke alerts, patient characteristics, telestroke care, and short-term outcomes pre- and post-SIP orders. METHODS: We conducted a cohort study in 21 stroke centers of an integrated healthcare system serving 4.4+ million members across Northern California. We included adult patients who presented with suspected acute stroke and were evaluated by telestroke between January 1, 2019, and May 9, 2020. SIP orders announced the week of March 15, 2020, created pre (January 1, 2019, to March 14, 2020) and post (March 15, 2020, to May 9, 2020) cohort for comparison. Main outcomes were stroke alert volumes and inpatient mortality for stroke. RESULTS: Stroke alert weekly volume post-SIP (mean, 98 [95% CI, 92-104]) decreased significantly compared with pre-SIP (mean, 132 [95% CI, 130-136]; P<0.001). Stroke discharges also dropped, in concordance with acute stroke alerts decrease. In total, 9120 patients were included: 8337 in pre- and 783 in post-SIP cohorts. There were no differences in patient demographics. Compared with pre-SIP, post-SIP patients had higher National Institutes of Health Stroke Scale scores (P=0.003), lower comorbidity score (P<0.001), and arrived more often by ambulance (P<0.001). Post-SIP, more patients had large vessel occlusions (P=0.03), and there were fewer stroke mimics (P=0.001). Discharge outcomes were similar for post-SIP and pre-SIP cohorts. CONCLUSIONS: In this cohort study, regional stroke alert and ischemic stroke discharge volumes decreased significantly in the early COVID-19 pandemic. Compared with pre-SIP, the post-SIP population showed no significant demographic differences but had lower comorbidity scores, more severe strokes, and more large vessel occlusions. The inpatient mortality was similar in both cohorts. Further studies are needed to understand the causes and implications of care avoidance to patients and healthcare systems.

Risk of Distal Embolization From tPA (Tissue-Type Plasminogen Activator) Administration Prior to Endovascular Stroke Treatment.

BACKGROUND AND PURPOSE: In large artery occlusion stroke, both intravenous (IV) tPA (tissue-type plasminogen activator) and endovascular stroke treatment (EST) are standard-of-care. It is unknown how often tPA causes distal embolization, in which a procedurally accessible large artery occlusion is converted to a more distal and potentially inaccessible occlusion. METHODS: We analyzed data from a decentralized stroke telemedicine program in an integrated healthcare delivery system covering 21 hospitals, with 2 high-volume EST centers. We captured all cases sent for EST and examined the relationship between IV tPA administration and the rate of distal embolization, the rate of target recanalization (modified Treatment in Cerebral Infarction scale 2b/3), clinical improvement before EST, and short-term and long-term clinical outcomes. RESULTS: Distal embolization before EST was quite common (63/314 [20.1%]) and occurred more often after IV tPA before EST (57/229 [24.9%]) than among those not receiving IV tPA (6/85 [7.1%]; P<0.001). Distal embolization was associated with an inability to attempt EST: after distal embolization, 26/63 (41.3%) could not have attempted EST because of the new clot location, while in cases without distal embolization, only 8/249 (3.2%) were unable to have attempted EST (P<0.001). Among patients who received IV tPA, 13/242 (5.4%) had sufficient symptom improvement that a catheter angiogram was not performed; 6/342 (2.5%) had improvement to within 2 points of their baseline NIHSS. At catheter angiogram, 2/229 (0.9%) of patients who had received tPA had complete recanalization without distal embolization. Both IV tPA and EST recanalization were associated with improved long-term outcome. CONCLUSIONS: IV tPA administration before EST for large artery occlusion is associated with distal embolization, which in turn may reduce the chance that EST can be attempted and recanalization achieved. At the same time, some IV tPA-treated patients show symptomatic improvement and complete recanalization. Because IV tPA is associated with both distal embolization and improved long-term clinical outcome, there is a need for prospective clinical trials testing the net benefit or harm of IV tPA before EST.

Cellular Interactions of Liposomes and PISA Nanoparticles during Human Blood Flow in a Microvascular Network.

A key concept in nanomedicine is encapsulating therapeutic or diagnostic agents inside nanoparticles to prolong blood circulation time and to enhance interactions with targeted cells. During circulation and depending on the selected application (e.g., cancer drug delivery or immune modulators), nanoparticles are required to possess low or high interactions with cells in human blood and blood vessels to minimize side effects or maximize delivery efficiency. However, analysis of cellular interactions in blood vessels is challenging and is not yet realized due to the diverse components of human blood and hemodynamic flow in blood vessels. Here, the first comprehensive method to analyze cellular interactions of both synthetic and commercially available nanoparticles under human blood flow conditions in a microvascular network is developed. Importantly, this method allows to unravel the complex interplay of size, charge, and type of nanoparticles on their cellular associations under the dynamic flow of human blood. This method offers a unique platform to study complex interactions of any type of nanoparticles in human blood flow conditions and serves as a useful guideline for the rational design of liposomes and polymer nanoparticles for diverse applications in nanomedicine.

Novel Telestroke Program Improves Thrombolysis for Acute Stroke Across 21 Hospitals of an Integrated Healthcare System.

BACKGROUND AND PURPOSE: Faster treatment with intravenous alteplase in acute ischemic stroke is associated with better outcomes. Starting in 2015, Kaiser Permanente Northern California redesigned its acute stroke workflow across all 21 Kaiser Permanente Northern California stroke centers to (1) follow a single standardized version of a modified Helsinki model and (2) have all emergency stroke cases managed by a dedicated telestroke neurologist. We examined the effect of Kaiser Permanente Northern California's Stroke EXpediting the PRrocess of Evaluating and Stopping Stroke program on door-to-needle (DTN) time, alteplase use, and symptomatic intracranial hemorrhage rates. METHODS: The program was introduced in a staggered fashion from September 2015 to January 2016. We compared DTN times for a seasonally adjusted 9-month period at each center before implementation to the corresponding 9-month calendar period from the start of implementation. The primary outcome was the DTN time for alteplase administration. Secondary outcomes included rate of alteplase administrations per month, symptomatic intracranial hemorrhage, and disposition at time of discharge. RESULTS: This study included 310 patients treated with alteplase in the pre-EXpediting the PRrocess of Evaluating and Stopping Stroke period and 557 patients treated with alteplase in the EXpediting the PRrocess of Evaluating and Stopping Stroke period. After implementation, alteplase administrations increased to 62/mo from 34/mo at baseline (P<0.001). Median DTN time decreased to 34 minutes after implementation from 53.5 minutes prior (P<0.001), and DTN time of <60 minutes was achieved in 87.1% versus 61.0% (P<0.001) of patients. DTN times <30 minutes were much more common in the Stroke EXpediting the PRrocess of Evaluating and Stopping Stroke period (40.8% versus 4.2% before implementation). There was no significant difference in symptomatic intracranial hemorrhage rates in the 2 periods (3.8% versus 2.2% before implementation; P=0.29). CONCLUSIONS: Introduction of a standardized modified Helsinki protocol across 21 hospitals using telestroke management was associated with increased alteplase administrations, significantly shorter DTN times, and no increase in adverse outcomes.

Elucidating the Influences of Size, Surface Chemistry, and Dynamic Flow on Cellular Association of Nanoparticles Made by Polymerization-Induced Self-Assembly.

The size and surface chemistry of nanoparticles dictate their interactions with biological systems. However, it remains unclear how these key physicochemical properties affect the cellular association of nanoparticles under dynamic flow conditions encountered in human vascular networks. Here, the facile synthesis of novel fluorescent nanoparticles with tunable sizes and surface chemistries and their association with primary human umbilical vein endothelial cells (HUVECs) is reported. First, a one-pot polymerization-induced self-assembly (PISA) methodology is developed to covalently incorporate a commercially available fluorescent dye into the nanoparticle core and tune nanoparticle size and surface chemistry. To characterize cellular association under flow, HUVECs are cultured onto the surface of a synthetic microvascular network embedded in a microfluidic device (SynVivo, INC). Interestingly, increasing the size of carboxylic acid-functionalized nanoparticles leads to higher cellular association under static conditions but lower cellular association under flow conditions, whereas increasing the size of tertiary amine-decorated nanoparticles results in a higher level of cellular association, under both static and flow conditions. These findings provide new insights into the interactions between polymeric nanomaterials and endothelial cells. Altogether, this work establishes innovative methods for the facile synthesis and biological characterization of polymeric nanomaterials for various potential applications.

A polymorphism in human MR1 is associated with mRNA expression and susceptibility to tuberculosis.

The MR1 antigen-presenting system is conserved among mammals and enables T cells to recognize small molecules produced by bacterial pathogens, including Mycobacterium tuberculosis (M.tb). However, it is not known whether MR1-mediated antigen presentation is important for protective immunity against mycobacterial disease. We hypothesized that genetic control of MR1 expression correlates with clinical outcomes of tuberculosis infection. We performed an MR1 candidate gene association study and identified an intronic single-nucleotide polymorphism (rs1052632) that was significantly associated with susceptibility to tuberculosis in a discovery and validation cohort of Vietnamese adults with tuberculosis. Stratification by site of disease revealed that rs1052632 genotype GG was strongly associated with the development of meningeal tuberculosis (odds ratio=2.99; 95% confidence interval (CI) 1.64-5.43; P=0.00006). Among patients with meningeal disease, absence of the G allele was associated with an increased risk of death (hazard ratio=3.86; 95% CI 1.49-9.98; P=0.005). Variant annotation tools using public databases indicate that rs1052632 is strongly associated with MR1 gene expression in lymphoblastoid cells (P=0.004) and is located within a transcriptional enhancer in epithelial keratinocytes. These data support a role for MR1 in the pathogenesis of human tuberculosis by revealing that rs1052632 is associated with MR1 gene expression and susceptibility to tuberculosis in Vietnam.