Chemical Stability of Lorazepam Oral Solution Repackaged in Plastic Oral Syringes at Room and Refrigerated Temperature.

Purpose: Generic lorazepam oral solution is supplied in a 30 mL multi-dose bottle requiring protection from light and refrigeration, with a beyond use date of 90 days once the bottle is opened. The repackaging of 1 mL doses of lorazepam oral solution into oral syringes allows for facilitated dispensing, yet no available data supports repackaging and storing lorazepam oral solution in syringes. The validation and application of a stability-indicating high-performance liquid chromatography with ultraviolet detection (HPLC-UV) method for the quantification of lorazepam allowed for the determination of the stability of lorazepam oral solution when stored in oral syringes. Methods: A stability-indicating HPLC-UV method was developed for the quantification of lorazepam in oral solution. The method was validated using guidance from USP < 1225 >. For the stability investigation, 2 mg/mL lorazepam oral solution was aliquoted into clear plastic oral syringes in 1 mLmilliliter doses from 2 multi-dose stock bottles and randomly allocated for storage in room temperature or refrigerated environment. Baseline lorazepam concentrations were measured on the day the study was initiated and designated as 100% initial concentration samples. Subsequent samples were analyzed in triplicate at time points of 24, 48, and 96 hours and 7, 10, 14, 21, 30, and 60 days. Results: The calibration curves on three non-consecutive days met the linearity criteria of R 2 > 0.99. Inter- day and intra-day precision and accuracy (percent relative standard deviation and percent error) were ≤2% over three days. During the stability investigation, percent initial concentration of lorazepam from room and refrigerated syringes remained above 90% for the duration of the study. Conclusion: The stability-indicating HPLC-UV method was successfully applied to the investigation of lorazepam oral solution stability when stored in syringes at room and refrigerated temperatures. The emergent need for use of lorazepam concentrate for inpatients and the restrictions of how the medication is supplied necessitated a need for the evaluation of repackaging into unit dose syringes for immediate availability from automated dispensing cabinets. Lorazepam oral solution stored in clear plastic syringes maintained greater than 90% initial concentration at both room and refrigerated temperatures for 60 days.

Impact of introducing a new biological matrix into a validated bioanalytical method: Focus on matrix protein content.

International guidance on bioanalytical method validation recommends the practice of partial validation when introducing a new matrix from the same species into a previously fully validated assay. Planning the partial validation protocol should include an evaluation of analyte chemistry, consideration of sample container materials, and a comparison of properties between the relevant biological matrices. Transition of a serum/plasma-validated bioanalytical method to analysis from a low-protein matrix, such as urine, cerebral spinal fluid, or oral fluid can result in inconsistent analyte recovery. The low recovery can potentially be mistaken for signal suppression or lack of drug stability and may be more pronounced in low-concentration or low-volume samples. In addition, adsorption and absorption interactions with containers may be exacerbated in low-protein matrices. Several possibilities exist for mitigating the impact of non-specific binding and low-protein matrices, including surfactants, bovine serum albumin, and ß-cyclodextrin. Finally, higher matrix protein can facilitate analyte stability. Given all this, matrix protein content should not be overlooked when anticipating a partial bioanalytical method validation.

Sprint-inspired One-on-One Post-Go-Live Training Session (Mini-Sprint) Improves Provider Electronic Health Record Efficiency and Satisfaction.

BACKGROUND: Inefficient electronic health record (EHR) usage increases the documentation burden on physicians and other providers, which increases cognitive load and contributes to provider burnout. Studies show that EHR efficiency sessions, optimization sprints, reduce burnout using a resource-intense five-person team. We implemented sprint-inspired one-on-one post-go-live efficiency training sessions (mini-sprints) as a more economical training option directed at providers. OBJECTIVES: We evaluated a post-go-live mini-sprint intervention to assess provider satisfaction and efficiency. METHODS: NorthShore University HealthSystem implemented one-on-one provider-to-provider mini-sprint sessions to optimize provider workflow within the EHR platform. The physician informaticist completed a 9-point checklist of efficiency tips with physician trainees covering schedule organization, chart review, speed buttons, billing, note personalization/optimization, preference lists, quick actions, and quick tips. We collected postsession survey data assessing for net promoter score (NPS) and open-ended feedback. We conducted financial analysis of pre- and post-mini-sprint efficiency levels and financial data. RESULTS: Seventy-six sessions were conducted with 32 primary care physicians, 28 specialty physicians, and 16 nonphysician providers within primary care and other areas. Thirty-seven physicians completed the postsession survey. The average NPS for the completed mini-sprint sessions was 97. The proficiency score had a median of 6.12 (Interquartile range (IQR): 4.71-7.64) before training, and a median of 7.10 (IQR: 6.25-8.49) after training. Financial data analysis indicates that higher level billing codes were used at a greater frequency post-mini-sprint. The revenue increase 12 months post-mini-sprint was $213,234, leading to a return of $75,559.50 for 40 providers, or $1,888.98 per provider in a 12-month period. CONCLUSION: Our data show that mini-sprint sessions were effective in optimizing efficiency within the EHR platform. Financial analysis demonstrates that this type of training program is sustainable and pays for itself. There was high satisfaction with the mini-sprint training modality, and feedback indicated an interest in further mini-sprint training sessions for physicians and nonphysician staff.

Safety and efficacy of dynamic catheter-directed cerebral digital subtraction angiography for diagnosis of bowhunter syndrome spectrum disorders: A systematic review of the literature.

INTRODUCTION: Dynamic catheter-directed cerebral digital subtraction angiography (dcDSA) is the gold standard for diagnosing dynamic vascular occlusion syndromes such as bowhunter syndrome (BHS). Nonetheless, concerns about its safety exist and no standardized protocols have been published to date. METHODS: We describe our methodology and insights regarding the use of dcDSA in patients with BHS. We also perform a systematic literature review to identify cases of typical and atypical presentations of BHS wherein dcDSA was utilized and report on any procedural complications related to dcDSA. RESULTS: Our study included 104 cases wherein dcDSA was used for the diagnosis of BHS. There were 0 reported complications of dcDSA. DcDSA successfully established diagnosis in 102 of these cases. Thirty-eight cases were deemed atypical presentations of BHS. Fourteen patients endorsed symptoms during neck flexion/extension. In eight cases, there was dynamic occlusion of bilateral vertebral arteries during a single maneuver. Three patients had multiple areas of occlusion along a single vertebral artery (VA). An anomalous entry of the VA above the C6 transverse foramen was observed in four patients. One patient had VA occlusion with neutral head position and recanalization upon contralateral lateral head tilt. CONCLUSION: Our study highlights the safety and diagnostic benefits of dcDSA in characterizing the broad spectrum of BHS pathology encountered in clinical practice. This technique offers a powerful means to evaluate changes in cerebral blood flow and cervical arterial morphology in real time, overcoming the constraints of static imaging methods. Our findings pave the way for further studies on dcDSA to enhance cross-sectional imaging methods for the characterization of BHS and other dynamic vascular occlusion syndromes.

A rare case of solitary, isolated dural metastasis from hepatocellular carcinoma mimicking a meningioma.

Background: Distinguishing an isolated metastatic dural tumor from a meningioma on imaging is challenging and may lead to a delay in treatment. Here, we present the first known case of isolated, solitary dural metastasis from hepatocellular carcinoma (HCC) mimicking a meningioma. Case Description: A 64-year-old male with a history of liver cirrhosis presented with a 5.8 cm enhancing left parafalcine hemorrhagic dural-based mass extending across the midline. Cerebral angiography revealed a distal left anterior pseudoaneurysm, and tumor contrast blush with feeders from the left ophthalmic and right middle meningeal artery. The pseudoaneurysm was successfully embolized to stop the bleeding, followed by an uneventful bi-coronal frontal craniotomy for falcine tumor resection to relieve brain compression. Histopathological analysis of the dural-based tumor showed poorly differentiated carcinoma with positive albumin in situ hybridization and cytokeratin tumor markers, consistent with dural metastases from HCC. Conclusion: When encountering a solitary, highly vascular mass bearing resemblance to a meningioma, it may be prudent to consider the possibility of a dural-based metastatic carcinoma.

An overview of Instructional approaches and decision-making strategies to curtail curricular overload.

OBJECTIVES: Curriculum overload often occurs when content is kept in the curriculum that may no longer be necessary to prepare students for professional practice. The overload becomes compounded by the addition of new content from the ever-changing professional practice needs and updates to accreditation standards. Challenges may occur when programs must first determine the "level" of proficiency a new graduate should attain and then determine the appropriate breadth and depth of educational outcomes in relation to proficiency, while examining what content should be retained from past curricula. Thus, the purpose of this manuscript is to summarize institutional approaches for making content delivery more effective and efficient with the goal of curtailing curriculum expansion. FINDINGS: Four key elements were consistently identified in the literature as important considerations to address curriculum overload - 1) communication and coordination among faculty, 2) incorporation of active learning strategies, 3) effective utilization of technology, and 4) minimizing faculty and student workload and cognitive burden. SUMMARY: Each pharmacy program will need to take an individualized approach in addressing curriculum overload; however, consideration of the aforementioned key elements can assist in making these decisions. With increased student engagement in the classroom, intentional design to reduce content and student workload, enhanced communication among faculty, and appropriate technology utilization, curriculum overload can be addressed at every level of pharmacy education.

A genome-wide association study of frailty identifies significant genetic correlation with neuropsychiatric, cardiovascular, and inflammation pathways.

Frailty is an aging-related clinical phenotype defined as a state in which there is an increase in a person's vulnerability for dependency and/or mortality when exposed to a stressor. While underlying mechanisms leading to the occurrence of frailty are complex, the importance of genetic factors has not been fully investigated. We conducted a large-scale genome-wide association study (GWAS) of frailty, as defined by the five criteria (weight loss, exhaustion, physical activity, walking speed, and grip strength) captured in the Fried Frailty Score (FFS), in 386,565 European descent participants enrolled in the UK Biobank (mean age 57 [SD 8] years, 208,481 [54%] females). We identified 37 independent, novel loci associated with the FFS (p < 5 × 10-8), including seven loci without prior described associations with other traits. The variants associated with FFS were significantly enriched in brain tissues as well as aging-related pathways. Our post-GWAS bioinformatic analyses revealed significant genetic correlations between FFS and cardiovascular-, neurological-, and inflammation-related diseases/traits, and subsequent Mendelian Randomization analyses identified causal associations with chronic pain, obesity, diabetes, education-related traits, joint disorders, and depressive/neurological, metabolic, and respiratory diseases. The GWAS signals were replicated in the Health and Retirement Study (HRS, n = 9,720, mean age 73 [SD 7], 5,582 [57%] females), where the polygenic risk score built from UKB GWAS was significantly associated with the FFS in HRS individuals (OR per SD of the score 1.27, 95% CI 1.22-1.31, p = 1.3 × 10-11). These results provide new insight into the biology of frailty by comprehensively evaluating its genetic architecture.

Difference in rural and urban Medicare prescription pattern for Parkinson's disease in Hawai'i.

Background: Medical management of Parkinson's Disease (PD) is becoming complex. Increasing evidence suggests that patients have better outcomes when they are managed by neurologists. However, access to neurologists can be limited in rural areas. Analysis of prescription pattern can provide insight into access gap rural patients face. Methods: This retrospective observational study used National Medicare Provider Utilization and Payment Data: Part D Prescriber Public Use Files from 2013 to 2018. Query was made for levodopa, dopamine agonists and other antiparkinsonian medications. The data elements obtained included drug name, number of prescribers, prescriber specialty, number of claims, number of standardized 30-day Part D prescriptions, and number of Medicare beneficiaries in the state of Hawai'i. Individual prescribing providers were categorized as urban or rural based on their cities of practice. Prescription patterns of urban and rural providers in Hawai'i as well as difference in provider specialty were compared, using standardized 30-day prescriptions as the primary measure of utilization. Results: Practice patterns differed between rural and urban areas. In rural Hawai'i, Rytary, Rotigoitne and selegiline were rarely prescribed. Levodopa percentage was higher in urban Hawai'i. In urban Hawai'i, 74.4% of the prescriptions were provided by movement disorders and general neurologists. In rural Hawai'i, 25.1% of the prescriptions were written by neurologists and 74.9% by general practitioners. Conclusions: In the state of Hawai'i, there is an urban-rural access gap to neurologists as evidenced by Medicare prescription pattern. Further study is needed to understand the reasons for rural-urban differences in prescription patterns and their impact on outcomes.

Development and Validation of a Liquid Chromatography-Mass Spectrometry Assay for Determination of Cromolyn Sodium in Skin Permeation Studies.

Cromolyn sodium (CS) is a mast cell stabilizer administered to treat allergic diseases. A topical system would sustain its delivery and may be designed for treatment of atopic dermatitis. Established HPLC protocols for detection of CS are time consuming and intensive, indicating the need for a more streamlined method. This study aimed at developing and validating a sensitive and selective LC-MS method for quantifying CS in skin permeation studies that was less time and resource demanding. The optimized method involved an isocratic mobile phase (10 mM NH4HCO3, pH 8.0, 90% and ACN, 10%) at a flow rate of 0.25 mL/min. Detection involved direct MS/MS channels with m/z 467.0255 (precursor) and m/z 379.0517 (fragment) using argon as the collision gas. CS calibrants were prepared in PBS, pH 7.4, and methanol for validation (0.1-2.5 µg/mL). To ensure no skin interference, dermatomed porcine skin was mounted on Franz diffusion cells that were analyzed after 24 h. The skin layers were also separated, extracted in methanol, and analyzed using the developed method. Retention time was 1.9 min and 4.1 min in methanol and buffer, respectively. No interfering peaks were observed from the receptor and skin extracts, and linearity was established between 0.1 and 2.5 µg/mL. Interday and intraday accuracy and precision were within the acceptable limit of ±20% at the LLOQ and ±15% at other concentrations. Overall, the simplified, validated method showed sensitivity in detecting CS in skin without interference and was applied to demonstrate quantification of drug in skin following 4% cromolyn sodium gel exposure.

Hospital Revisits for Post-Ischemic Stroke Epilepsy after Acute Stroke Interventions.

OBJECTIVES: Improvements in acute stroke care have led to an increase in ischemic stroke survivors, who are at risk for development of post-ischemic stroke epilepsy (PISE). The impact of therapies such as thrombectomy and thrombolysis on risk of hospital revisits for PISE is unclear. We utilized administrative data to investigate the association between stroke treatment and PISE-related visits. MATERIALS AND METHODS: Using claims data from California, New York, and Florida, we performed a retrospective analysis of adult survivors of acute ischemic strokes. Patients with history of epilepsy, trauma, infections, or tumors were excluded. Included patients were followed for a primary outcome of revisits for seizures or epilepsy. Cox proportional hazards regression was used to identify covariates associated with PISE. RESULTS: In 595,545 included patients (median age 74 [IQR 21], 52% female), the 6-year cumulative rate of PISE-related revisit was 2.20% (95% CI 2.16-2.24). In multivariable models adjusting for demographics, comorbidities, and indicators of stroke severity, IV-tPA (HR 1.42, 95% CI 1.31-1.54, p<0.001) but not MT (HR 1.62, 95% CI 0.90-1.50, p=0.2) was associated with PISE-related revisit. Patients who underwent decompressive craniectomy experienced a 2-fold increase in odds for returning with PISE (HR 2.35, 95% CI 1.69-3.26, p<0.001). In-hospital seizures (HR 4.06, 95% CI 3.76-4.39, p<0.001) also elevated risk for PISE. SIGNIFICANCE: We demonstrate that ischemic stroke survivors who received IV-tPA, underwent decompressive craniectomy, or experienced acute seizures were at increased risk PISE-related revisit. Close attention should be paid to these patients with increased potential for long-term development of and re-hospitalization for PISE.

Genetically Determined Low-Density Lipoprotein Cholesterol and Risk of Subarachnoid Hemorrhage.

We evaluated whether genetically elevated low-density lipoprotein cholesterol (LDL-C) levels are associated with lower risk of intracranial aneurysms and subarachnoid hemorrhage (IA/SAH). We conducted a 2-sample Mendelian randomization (MR) study. Our primary analysis used the inverse-variance weighted method. In secondary analyses, we implemented the MR-PRESSO method, restricted our analysis to LDL-C-specific instruments, and performed multivariate MR. A 1-mmol/l increase in genetically instrumented LDL-C levels was associated with a 17% lower risk of IA/SAH (odds ratio = 0.83, 95% confidence interval = 0.73-0.94, p = 0.004). Results remained consistent in secondary and multivariate analyses (all p < 0.05). Our results provide evidence for an inverse causal relationship between LDL-C levels and risk of IA/SAH. ANN NEUROL 2022;91:145-149.

The hormonal environment and estrogen receptor signaling alters Chlamydia muridarum infection in vivo.

Genital Chlamydia is the most common bacterial sexually transmitted infection in the United States and worldwide. Previous studies indicate that the progression of chlamydial infection is influenced by various factors, including the female sex hormones estrogen and progesterone. Sex hormone levels naturally fluctuate in women throughout their menstrual cycle. Varying concentrations of estrogen and progesterone may impact the progression of chlamydial infection and the host's immune response to Chlamydia. Estrogen signals through estrogen receptors (ERs), ERα and ERß. These receptors are similar in structure and function, but are differentially expressed in tissues throughout the body, including the genital tract and on cells of the immune system. In this study, we used ovariectomized (OVT) BALB/c mice to investigate the impact of long-term administration of physiologically relevant concentrations of estrogen (E2), progesterone (P4), or a combination of E2/P4 on the progression of and immune response to C. muridarum infection. Additionally, we used ERα and ERß knockout C57/BL6 mice to determine the how ERs affect chlamydial infection and the resulting immune response. Estrogen exposure prevented C. muridarum infection in vaginally infected OVT mice exposed to E2 alone or in combination with P4, while OVT or Sham mice exposed to hormone free, P4 or depo-medroxyprogesterone acetate shed similar amounts of chlamydiae. The hormonal environment also altered T cell recruitment and IFNϵ production the genital tracts of infected OVT and Sham mice on day 10 post infection. The absence of ERα, but not ERß, in ER knockout mouse strains significantly changed the timing of C. muridarum infection. ERαKO mice shed significantly more chlamydiae at day 3 post infection and resolved the infection faster than WT or ERßKO animals. At day 9 post infection, flow cytometry showed that ERαKO mice had more T cells present and targeted RNA sequencing revealed increased expression of CD4 and FOXP3, suggesting that ERαKO mice had increased numbers of regulatory T cells compared to ERßKO and WT mice. Mock and chlamydia-infected ERαKO mice also expressed more IFNϵ early during infection. Overall, the data from these studies indicate that sex hormones and their receptors, particularly ERα and ERß, differentially affect C. muridarum infection in murine models of infection.

Stability of Ampicillin in Normal Saline Following Refrigerated Storage and 24-Hour Pump Recirculation.

OBJECTIVE: Use of ampicillin in outpatient parenteral antimicrobial therapy (OPAT) has historically been complicated by frequent dosing and limited stability. The purpose of this study was to evaluate stability of ampicillin using high-pressure liquid chromatography (HPLC) in an OPAT dosing model using continuous infusion at room temperature over 24 hours immediately following preparation compared with batches stored under refrigeration for 24 hours, 72 hours, and 7 days. METHODS: An HPLC method was developed and validated as stability indicating using guidance in USP general Chapter <1225>. Four ampicillin batches were prepared for each experimental condition (immediate use and refrigerated storage for 24 hours, 72 hours, and 7 days). A pump was used to recirculate the solutions through medical-grade tubing for 24 hours. Triplicate 1-mL aliquots were removed from each batch at time 0, 4, 8, 12, and 24 hours and analyzed for ampicillin concentration. RESULTS: Each batch was assayed for initial concentration (20.34-21.50 mg/mL), and percent recovery compared with that concentration thereafter. For the duration of infusion, the average recoveries were 96.4%, 95.8%, 94.6%, and 90.3% for immediate use, 24-hour storage, 72-hour storage, and 7-day storage, respectively. The recovery remained above 90% for all batches and time points, except for 7-day storage, which fell below 90% after 4 hours of circulation. CONCLUSION: Ampicillin can be prepared and stored in a refrigerator for up to 72 hours prior to continuously infusing at room temperature over 24 hours with less than a 10% loss of potency over the dosing period. This model supports twice weekly OPAT delivery of ampicillin.

Pharmacokinetics of Synthetic Cathinones Found in Bath Salts in Mouse Brain and Plasma Using High-Pressure Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND AND OBJECTIVES: Approximately 10 years ago, "bath salts" became popular as legal alternatives to the psychostimulants cocaine and the amphetamines. These products contained synthetic cathinones, including 3,4-methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4-methylenedioxymethcathinone (methylone). Most preclinical investigations have only assessed the effects of these synthetic cathinones independently; however, case reports and Drug Enforcement Administration (DEA) studies indicate that bath salts contain mixtures of these substances. In this study, we examine the pharmacokinetic interactions of the drug combination. We hypothesized that combined exposure to MDPV, mephedrone, and methylone would result in increased drug concentrations and enhanced total drug concentrations when compared to individual administration. METHODS: Adolescent male Swiss-Webster mice were injected intraperitoneally with either 10 mg/kg MDPV, 10 mg/kg mephedrone, 10 mg/kg methylone, or 10 mg/kg combined MDPV, mephedrone, and methylone. Following injection, brains and plasma were collected at 1, 10, 15, 30, 60, and 120 min. Drugs were extracted via solid-phase extraction, and concentrations were determined using a previously published high-pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. RESULTS: All drugs crossed the blood-brain barrier quickly. For methylone, the maximal concentration (Cmax) and the total drug exposure [as represented by the area under the concentration-time curve (AUC)] were significantly higher when combined with mephedrone and MDPV in both matrices (2.89-fold increase for both Cmax and AUC with combined treatment). For mephedrone, the Cmax was unchanged, but the AUC in brain was increased when in combination by approximately 34%. Interestingly, for MDPV, the Cmax was unchanged, yet the AUC was higher when MDPV was administered individually (there was a 62% decrease in AUC with combined treatment). CONCLUSIONS: The pharmacokinetics of methylone, mepedrone, and MDPV are altered when the drugs are used in combination. These data provide insight into the consequences of co-exposure to synthetic cathinones in popular bath salt products.

Cardiovascular Health Disparities in Racial and Other Underrepresented Groups: Initial Results From the All of Us Research Program.

Background All of Us is a novel research program that aims to accelerate research in populations traditionally underrepresented in biomedical research. Our objective was to evaluate the burden of cardiovascular disease (CVD) in broadly defined underrepresented groups. Methods and Results We evaluated the latest data release of All of Us. We conducted a cross-sectional analysis combining survey and electronic health record data to estimate the prevalence of CVD upon enrollment in underrepresented groups defined by race, ethnicity, age (>75 years), disability (not able to carry out everyday physical activities), sexual orientation and gender identity lesbian, gay, bisexual, transgender, queer, intersex, and asexual (LGBTQIA+), income (annual household income <$35 000 US dollars) and education (less than a high school degree). We used multivariate logistic regression to estimate the adjusted odds ratio (OR) and product terms to test for interaction. The latest All of Us data release includes 315 297 participants. Of these, 230 577 (73%) had information on CVD and 17 958 had CVD (overall prevalence, 7.8%; 95% CI, 7.7-7.9). Multivariate analyses adjusted by hypertension, hyperlipidemia, type 2 diabetes mellitus, body mass index, and smoking indicated that, compared with White participants, Black participants had a higher adjusted odds of CVD (OR, 1.21; 95% CI, 1.16-1.27). Higher adjusted odds of CVD were also observed in underrepresented groups defined by other factors, including age >75 years (OR, 1.90; 95% CI, 1.81-1.99), disability (OR, 1.60; 95% CI, 1.53-1.68), and income <$35 000 US dollars (OR, 1.22; 95% CI, 1.17-1.27). Sex significantly modified the odds of CVD in several of the evaluated groups. Conclusions Among participants enrolled in All of Us, underrepresented groups defined based on race, ethnicity and other factors have a disproportionately high burden of CVD. The All of Us research program constitutes a powerful platform to accelerate research focused on individuals in underrepresented groups.

Stroke Disparities Among Nonracial Minorities in the All of Us Research Program.

[Figure: see text].

Endovascular Treatment of Infective Endocarditis-Related Acute Large Vessel Occlusion Stroke.

OBJECTIVES: Embolic stroke is a frequent complication of infective endocarditis yet lacks acute treatment as intravenous thrombolysis should be avoided due to high risk of intracerebral hemorrhage. Mechanical thrombectomy for large vessel occlusion may be a promising treatment but there is limited data on safety outcomes in infective endocarditis. MATERIALS AND METHODS: In this multi-center retrospective case series, we reviewed data from patients with infective endocarditis-related large vessel occlusion who underwent mechanical thrombectomy in 9 US hospitals. RESULTS: We identified 15 patients at 9 hospitals. A minority presented with signs suggesting infection (2 patients (14%) had fever, 7 (47%) were tachycardic, 2 (13%) were hypotensive, and 8 (53%) had leukocytosis). The median National Institute of Health Stroke Score decreased from 19 (range 9-25) at presentation to 7 post-thrombectomy (range 0-22, median best score post-thrombectomy), and the median modified Rankin Scale on or after discharge for survivors was 3 (range 0-6). Approximately 57% of patients had a modified Rankin Scale between 0 and 3 on or after discharge. Hemorrhagic transformation was observed in 7/15 (47%). The mechanical thrombectomy group had 2/9 petechial hemorrhagic transformation (22%), compared to 4/6 parenchymal hematomas (67%) in the tissue plasminogen activator + mechanical thrombectomy group. CONCLUSIONS: Our findings suggest that patients with large vessel occlusion due to infective endocarditis may not present with overt signs of infection. Mechanical thrombectomy may be an effective treatment in this patient population for whom intravenous thrombolysis should be avoided.

Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage.

BACKGROUND/OBJECTIVE: There are limited data on the risks and benefits of using andexanet alfa (AA) in comparison with four-factor prothrombin complex concentrate (4F-PCC) to reverse factor Xa inhibitors (FXi) associated intracranial hemorrhage (ICH). We sought to describe our experience with AA or 4F-PCC in patients with oral FXi-related traumatic and spontaneous ICH. METHODS: We conducted a retrospective review of consecutive adult patients with FXi-related ICH who received AA or 4F-PCC. FXi-related ICH cases included traumatic and spontaneous intracranial hemorrhages. Our primary analysis evaluated ICH stability on head computed tomography scan (CT), defined as a similar amount of blood from the initial scan at the onset of ICH to subsequent scans, at 6-h and 24-h post-administration of AA or 4F-PCC. For the subset of spontaneous intraparenchymal hemorrhages, volume was measured at 6-h and 24-h post-reversal. In secondary analyses, we evaluated good functional outcome at discharge, defined as a Modified Rankin Score of less than 3, and the incidence of thrombotic events after AA or 4F-PCC adminstration, during hospitalization. RESULTS: A total of 44 patients (16 traumatic and 28 spontaneous ICH) with median age of 79 years [72-86], 36% females, with a FXi-related ICH, were included in this study. The majority of spontaneous ICHs were intraparenchymal 19 (68%). Twenty-eight patients (64%) received AA and 16 patients (36%) received 4F-PCC. There was no difference between AA and 4F-PCC in terms of CT stability at 6 h (21 [78%] vs 10 [71%], p = 0.71) and 24 h (15 [88%] vs 6 [60%], p = 0.15). In a subgroup of patients with spontaneous intraparenchymal hemorrhage, there was no difference in the degree of achieved hemostasis based on hematoma volume between AA and 4F-PCC at 6 h (9.3 mL [6.9-26.4] vs 10 mL [9.4-22.1], adjusted p = 0. 997) and 24-h (9.2 mL [6.1-18.8] vs 9.9 [9.4-21.1], adjusted p = 1). The number of patients with good outcome based on mRS on discharge were 10 (36%) and 6 (38%) in the AA and 4F-PCC groups, respectively (adjusted p = 0.81). The incidence of thromboembolic events was similar in the AA and 4F-PCC groups (2 [7%] vs 0, p = 0.53). CONCLUSION: In this limited sample of patients, we found no difference in neuroimaging stability, functional outcome and thrombotic events when comparing AA and 4F-PCC in patients with FXi-related ICH. Since our analysis is likely underpowered, a multi-center collaborative network devoted to this question is warranted.