Inactivated Four-Factor Prothrombin Complex Concentrate Dosing Practices for Reversal of Warfarin-Related Intracranial Hemorrhage.

BACKGROUND/OBJECTIVE: Inactivated four-factor prothrombin complex concentrate (I4F-PCC, Kcentra®) has become an important agent for the urgent or emergent reversal of bleeding associated with vitamin K antagonists such as warfarin. There is recognized inter-institutional variability with the use of I4F-PCC, especially as it relates to dosing practices. We sought to characterize variations in I4F-PCC dosing practices and their impact on patient outcomes and describe overall real-world clinical practice surrounding I4F-PCC utilization in the context of the management of warfarin-related intracranial hemorrhage (ICH). METHODS: This is a multicenter retrospective pragmatic registry study of adult patients admitted at a participating study site between January 1, 2014, and December 31, 2015, who received I4F-PCC for reversal of warfarin-related ICH. Practices around warfarin-related ICH reversal in context of I4F-PCC utilization are described, including repeat I4F-PCC dosing, adjunctive reversal agents, and dose rounding policies (i.e., rounding doses to nearest vial size vs preparing exact/unrounded doses). All research was approved by local human investigation committees at each institution. RESULTS: Seventeen institutions contributed data on 528 patients to this registry. These institutions were primarily urban centers (74%), located in the southeast USA (47%), with Level 1 Trauma designation (79%), and with Comprehensive Stroke Center designation (74%). Most patients included in the study had sustained a non-traumatic ICH (68%), had a median admission GCS of 14 (IQR 7-15), and were receiving warfarin for atrial fibrillation (57.4%). There was substantial time latency between baseline INR and I4F-PCC (median 2.4 h, IQR 1.4-4.5 h). Most patients received adjunctive reversal agents, including vitamin K (89.5%) and fresh frozen plasma (FFP) (31.9%). A smaller proportion (6.0%) of patients received repeat I4F-PCC dosing. The median ICU length of stay (LOS) was 3 days (IQR 2-7 days), median hospital LOS was 6 days (IQR 3-12 days), and overall mortality rate was 28.8%. For institutions rounding doses to the nearest vial size, the first post-I4F-PCC dose INR was statistically but not clinically significantly lower than for institutions without vial size dose rounding, with comparable degrees of INR reduction from baseline. No differences were observed between dose rounding cohorts in adverse effects, ICU or hospital LOS, modified Rankin score at discharge, or mortality rates. CONCLUSIONS: Most patients received single doses of I4F-PCC, with adjunctive reversal agents and rounding doses to vial size. The time difference from baseline INR to factor product administration is a potential opportunity for process improvement in the management of warfarin-related ICH.

Current Practices of Intraventricular Antibiotic Therapy in the Treatment of Meningitis and Ventriculitis: Results from a Multicenter Retrospective Cohort Study.

BACKGROUND: Central nervous system (CNS) infections are particularly prevalent in the adult neurocritical care patient population and are associated with significant morbidity and mortality. Factors relevant to the nature of CNS infections pose significant challenges to clinicians treating afflicted patients. Intraventricular (IVT) administration of antibiotics may offer several benefits over systemic therapy; however, the outcomes and current practices of such treatments are poorly described in the literature. OBJECTIVE: To describe current practices and outcomes of patients receiving intraventricular antibiotic treatment for CNS infections in neurological intensive care units of academic medical centers nationwide. METHODS: A retrospective cohort study was conducted on patients admitted to intensive care units who received IVT antibiotic treatment at participating centers in the USA between January 01, 2003, and December 31, 2013. Clinical and laboratory parameters, microbiology, surgical and antimicrobial management, and treatment outcomes were collected and described. RESULTS: Of the 105 patients included, all received systemic antimicrobial therapy along with at least one dose of IVT antimicrobial agents. Intraventricular vancomycin was used in 52.4% of patients. The average dose was 12.2 mg/day for a median duration of 5 days. Intraventricular aminoglycosides were used in 47.5% of the patients, either alone or in combination with IVT vancomycin. The average dose of gentamicin/tobramycin was 6.7 mg/day with a median duration of 6 days. Overall mortality was 18.1%. Cerebrospinal fluid (CSF) culture sterilization occurred in 88.4% of the patients with a rate of recurrence or persistence of positive cultures of 9.5%. CONCLUSION: Intraventricular antimicrobial agents resulted in a high CSF sterilization rate. Contemporary use of this route typically results in a treatment duration of less than a week. Prospective studies are needed to establish the optimal patient population, as well as the efficacy and safety of this route of administration.

Correction to: Phase 2 Open-Label Trial Investigating Percutaneous Laser Ablation for Treatment of Early-Stage Breast Cancer: MRI, Pathology, and Outcome Correlations.

The article "Phase 2 Open-Label Trial Investigating Percutaneous Laser Ablation for Treatment of Early-Stage Breast Cancer: MRI, Pathology, and Outcome Correlations", written by Barbara Schwartzberg et al., was originally published electronically on the publisher's internet portal (currently SpringerLink) on July 9, 2018, without open access.

Phase 2 Open-Label Trial Investigating Percutaneous Laser Ablation for Treatment of Early-Stage Breast Cancer: MRI, Pathology, and Outcome Correlations.

BACKGROUND: An institutional review board-approved, multicenter clinical trial was designed to determine the efficacy and outcome of percutaneous laser ablation (PLA) in the treatment of invasive ductal breast carcinoma (IDC). Post-ablation magnetic resonance imaging (MRI) was compared with surgical pathology in evaluation of residual post-ablation IDC and ductal carcinoma in situ. METHODS: Patients with a single focus of IDC 20 mm or smaller by pre-ablation MRI were treated with PLA. The patients underwent a 28-day post-ablation MRI, followed by surgical resection. Cell viability criteria were applied to pre- and post-ablation pathology specimens, which evaluated hematoxylin-eosin (H&E), cytokeratin (CK) 8/18, estrogen receptor, and Ki67 staining patterns. RESULTS: In this study, 61 patients were reported as the intention-to-treat cohort for determination of PLA efficacy. Of these 61 patients, 51 (84%) had complete tumor ablation confirmed by pathology analysis. One subject's MRI imaging was not performed per protocol, which left 60 subjects evaluable for MRI pathology correlation. Five patients (8.3%) had residual IDC shown by both MRI and pathology. Post-ablation discordance was noted between MRI and pathology, with four patients (6.7%) false-positive and four patients (6.7%) false-negative. The negative predictive value (NPV) of MRI for all the patients was 92.2% (95% confidence interval [CI], 71.9-91.9%). Of the 47 patients (97.9%) with tumors 15 mm or smaller, 46 were completely ablated, with an MRI NPV of 97.7% (95% CI, 86.2-99.9%). CONCLUSIONS: Percutaneous laser ablation is a potential alternative to surgery for treatment of early-stage IDC. Strong correlations exist between post-ablation MRI and pathologic alterations in CK8/18, ER, and Ki67 staining.

Initial Experience of Tomosynthesis-Guided Vacuum-Assisted Biopsies of Tomosynthesis-Detected (2D Mammography and Ultrasound Occult) Architectural Distortions.

OBJECTIVE: As experience and aptitude in digital breast tomosynthesis (DBT) have increased, radiologists are seeing more areas of architectural distortion (AD) on DBT images compared with standard 2D mammograms. The purpose of this study is to report our experience using tomosynthesis-guided vacuum-assisted biopsies (VABs) for ADs that were occult at 2D mammography and ultrasound and to analyze the positive predictive value for malignancy. MATERIALS AND METHODS: We performed a retrospective review of 34 DBT-detected ADs that were occult at mammography and ultrasound. RESULTS: We found a positive predictive value of 26% (nine malignancies in 34 lesions). Eight of the malignancies were invasive and one was ductal carcinoma in situ. The invasive cancers were grade 1 (4/8; 50%), grade 2 (2/8; 25%), or grade 3 (1/8; 13%); information about one invasive cancer was not available. The mean size of the invasive cancers at pathologic examination was 7.5 mm (range, 6-30 mm). CONCLUSION: Tomosynthesis-guided VAB is a feasible method to sample ADs that are occult at 2D mammography and ultrasound. Tomosynthesis-guided VAB is a minimally invasive method that detected a significant number of carcinomas, most of which were grade 1 cancers. Further studies are needed.

Antiepileptic drugs in critically ill patients.

BACKGROUND: The incidence of seizures in intensive care units ranges from 3.3% to 34%. It is therefore often necessary to initiate or continue anticonvulsant drugs in this setting. When a new anticonvulsant is initiated, drug factors, such as onset of action and side effects, and patient factors, such as age, renal, and hepatic function, should be taken into account. It is important to note that the altered physiology of critically ill patients as well as pharmacological and nonpharmacological interventions such as renal replacement therapy, extracorporeal membrane oxygenation, and target temperature management may lead to therapeutic failure or toxicity. This may be even more challenging with the availability of newer antiepileptics where the evidence for their use in critically ill patients is limited. MAIN BODY: This article reviews the pharmacokinetics and pharmacodynamics of antiepileptics as well as application of these principles when dosing antiepileptics and monitoring serum levels in critically ill patients. The selection of the most appropriate anticonvulsant to treat seizure and status epileptics as well as the prophylactic use of these agents in this setting are also discussed. Drug-drug interactions and the effect of nonpharmacological interventions such as renal replacement therapy, plasma exchange, and extracorporeal membrane oxygenation on anticonvulsant removal are also included. CONCLUSION: Optimal management of antiepileptic drugs in the intensive care unit is challenging given altered physiology, polypharmacy, and nonpharmacological interventions, and requires a multidisciplinary approach where appropriate and timely assessment, diagnosis, treatment, and monitoring plans are in place.

Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine.

BACKGROUND: The use of antithrombotic agents, including anticoagulants, antiplatelet agents, and thrombolytics has increased over the last decade and is expected to continue to rise. Although antithrombotic-associated intracranial hemorrhage can be devastating, rapid reversal of coagulopathy may help limit hematoma expansion and improve outcomes. METHODS: The Neurocritical Care Society, in conjunction with the Society of Critical Care Medicine, organized an international, multi-institutional committee with expertise in neurocritical care, neurology, neurosurgery, stroke, hematology, hemato-pathology, emergency medicine, pharmacy, nursing, and guideline development to evaluate the literature and develop an evidence-based practice guideline. Formalized literature searches were conducted, and studies meeting the criteria established by the committee were evaluated. RESULTS: Utilizing the GRADE methodology, the committee developed recommendations for reversal of vitamin K antagonists, direct factor Xa antagonists, direct thrombin inhibitors, unfractionated heparin, low-molecular weight heparin, heparinoids, pentasaccharides, thrombolytics, and antiplatelet agents in the setting of intracranial hemorrhage. CONCLUSIONS: This guideline provides timely, evidence-based reversal strategies to assist practitioners in the care of patients with antithrombotic-associated intracranial hemorrhage.

Survey of transplant-related pharmacy services at large comprehensive transplant centers in the United States.

CONTEXT: United Network for Organ Sharing (UNOS) 2011 bylaws and Centers for Medicare and Medicaid Services (CMS) regulations require a transplant pharmacist to be an active participant in the care of transplant patients. Transplant centers must be members in good standing with UNOS in order to perform transplants and must be certified by CMS to participate with Medicare. OBJECTIVE: To identify characteristics of transplant-related pharmacy services at comprehensive transplant centers. DESIGN: Survey regarding number of full-time equivalent (FTE) transplant pharmacists relative to number of annual transplants, transplant pharmacy model, roles in inpatient and clinic environments, training and specialization, funding sources, and expansion plans.Participants-Surveys were received from 14 (74%) of 19 identified centers that performed 200 to 400 kidney, liver, pancreas, simultaneous kidney/pancreas, heart, and lung transplants in 2010, representing 55 transplant pharmacists. RESULTS: A mean of 325 transplants were performed in 2010 at the surveyed centers. The mean number of pharmacist FTEs was 4.25, which yielded a transplant-to-pharmacist ratio of 76.5. Nine centers (64%) practiced in a pharmacy specialist-only model, 12 (86%) practiced in a service-based fashion, and 10 (71%) saw patients in clinic. Fifty-four pharmacists (98%) had obtained a PharmD degree, 45 (82%) had completed 1 postgraduate year, and 28 (51%) had completed 2 postgraduate years of training. Nine centers (64%) funded FTEs solely through the pharmacy department. Ten centers (71%) plan to expand transplant pharmacist staff by a mean of 1.4 FTEs. CONCLUSIONS: Large comprehensive transplant centers use multiple transplant pharmacists to perform patient care in the inpatient and outpatient environments. Most centers plan to expand FTEs. Further characterization of transplant pharmacists appears warranted.

FDA's dilemma with the aducanumab approval: public pressure and hope, surrogate markers and efficacy, and possible next steps.

Accelerating Food and Drug Administration (FDA) product approval to market based on surrogate markers in the absence of proven efficacy creates a risk of adverse outcomes for affected patients, even in response to a life-threatening condition, such as in this case, Alzheimer's disease. FDA's recent unexpected approval of aducanumab, despite the unified opposition of its own highly respected advisory committee after the early termination of two efficacy trials, creates the potential risk of adverse effects and lack of clinical efficacy at very high costs. In view of these concerns, a thorough review of the issues and pressures that led to this decision is worth the careful consideration of the clinical and scientific communities with regard to whether this approval represents a calculated and balanced compassionate decision versus a disturbing precedent.

PACS-integrated machine learning breast density classifier: clinical validation.

OBJECTIVE: To test the performance of a novel machine learning-based breast density tool. The tool utilizes a convolutional neural network to predict the BI-RADS based density assessment of a study. The clinical density assessments of 33,000 mammographic examinations (164,000 images) from one academic medical center (Site A) were used for training. MATERIALS AND METHODS: This was an IRB approved HIPAA compliant study performed at two academic medical centers. The validation data set was composed of 500 studies from one site (Site A) and 700 from another (Site B). At Site A, each study was assessed by three breast radiologists and the majority (consensus) assessment was used as truth. At Site B, if the tool agreed with the clinical reading, then it was considered to have correctly predicted the clinical reading. In cases where the tool and the clinical reading disagreed, then the study was evaluated by three radiologists and the consensus reading was used as the clinical reading. RESULTS: For the classification into the four categories of the Breast Imaging Reporting and Data System (BI-RADS®), the AI classifier had an accuracy of 84.6% at Site A and 89.7% at Site B. For binary classification (dense vs. non-dense), the AI classifier had an accuracy of 94.4% at Site A and 97.4% at Site B. In no case did the classifier disagree with the consensus reading by more than one category. CONCLUSIONS: The automated breast density tool showed high agreement with radiologists' assessments of breast density.

Validity and reliability of The Johns Hopkins Adapted Cognitive Exam for critically ill patients.

OBJECTIVE: To validate The Johns Hopkins Adapted Cognitive Exam designed to assess and quantify cognition in critically ill patients. DESIGN: Prospective cohort study. SETTING: Neurosciences, surgical, and medical intensive care units at The Johns Hopkins Hospital. PATIENTS: One hundred six adult critically ill patients. INTERVENTIONS: One expert neurologic assessment and four measurements of the Adapted Cognitive Exam (all patients). Four measurements of the Folstein Mini-Mental State Examination in nonintubated patients only. Adapted Cognitive Exam and Mini-Mental State Examination were performed by 76 different raters. MEASUREMENTS AND MAIN RESULTS: One hundred six patients were assessed, 46 intubated and 60 nonintubated, resulting in 424 Adapted Cognitive Exam and 240 Mini-Mental State Examination measurements. Criterion validity was assessed by comparing Adapted Cognitive Exam with a neurointensivist's assessment of cognitive status (ρ = 0.83, p < .001). Ordinal logistic regression established optimal predicted cut points for cognitive status classification (≤ 28 = severely impaired, 29-55 = moderately impaired, ≥ 56 = mildly impaired or normal). Using these cut points, the Adapted Cognitive Exam appropriately classified cognitive status 90% of the time. Construct validity was assessed by comparing Adapted Cognitive Exam with Mini-Mental State Examination in nonintubated patients (ρ = 0.81, p < .001). Face validity was assessed by surveying raters who used both the Adapted Cognitive Exam and Mini-Mental State Examination and indicated the Adapted Cognitive Exam was an accurate reflection of the patient's cognitive status, more sensitive a marker of cognition than the Mini-Mental State Examination, and easy to use. The Adapted Cognitive Exam demonstrated excellent interrater reliability (intraclass correlation coefficient = 0.997; 95% confidence interval 0.997-0.998) and interitem reliability of each of the five subscales of the Adapted Cognitive Exam and Mini-Mental State Examination (Cronbach's α: range for Adapted Cognitive Exam = 0.83-0.88; range for Mini-Mental State Examination = 0.72-0.81). CONCLUSION: The Adapted Cognitive Exam is the first valid and reliable examination for the assessment and quantification of cognition in critically ill patients. It provides a useful, objective tool that can be used by any member of the interdisciplinary critical care team to support clinical assessment and research efforts.

Improving door-to-antibiotic time in severely septic emergency department patients.

BACKGROUND: The Surviving Sepsis Campaign (SSC) guidelines recommend that broad-spectrum antibiotics be administered to severely septic patients within 3 h of emergency department (ED) admission. Despite the well-established evidence regarding the benefit of timely antibiotics, adoption of the SSC recommendation into daily clinical practice has been slow and sporadic. STUDY OBJECTIVE: To study the impact of storing broad-spectrum antibiotics in an ED automated dispensing cabinet (ADC) on the timeliness of antibiotic administration in severely septic patients presenting to the ED. METHODS: Retrospective observational study of timeliness of antibiotic administration in severely septic patients presenting to a community ED before and after adding broad-spectrum antibiotics to the ED ADC. Data on 56 patients before and 54 patients after the intervention were analyzed. The primary outcome measure was mean order-to-antibiotic time. Secondary outcome measures included mean door-to-antibiotic time and percentage of patients receiving antibiotics within 3 h. RESULTS: The final analysis was on 110 patients. Order-to-antibiotic administration time was reduced by 29 min post-intervention (55 min vs. 26 min, 95% confidence interval [CI] 12.5-45.19). Mean door-to-antibiotic time was also reduced by 70 min (167 min vs. 97 min, 95% CI 37.53-102.29). The percentage of severely septic patients receiving antibiotics within 3h of arrival to the ED increased from 65% pre-intervention to 93% post-intervention (95% CI 0.12-0.42). CONCLUSION: Storing key antibiotics in an institution's severe sepsis antibiogram in the ED ADC can significantly reduce order-to-antibiotic times and increase the percentage of patients receiving antibiotics within the recommended 3 h of ED arrival.

Differential expression of prognostic biomarkers between interval and screen-detected breast cancers: does age or family history matter?

The aim of this study was to compare tumor expression of prognostic biomarkers between interval breast cancers and screen-detected breast cancers overall, and according to age at diagnosis and familial risk. Tissue micro-arrays were constructed from 98 breast cancers (47 interval and 51 screen-detected) diagnosed in women in the Cancer Genetics Network. Arrays were immuno-stained to compare protein expression of six biomarkers including estrogen and progesterone receptor (ER/PR), Her2/neu, EGFR, cytokeratin 5/6, and Ki67. Fisher's Exact test was used to compare expression between interval and screen-detected cancers. Interval cancers were larger (P = 0.04), higher stage (P < 0.001), and more likely to have lobular histology (P = 0.01) than screen-detected cancers. Overall, interval cancers more often overexpressed EGFR (P = 0.01) and were somewhat more likely to be ER- (55% vs. 43%, P = 0.3), and triple negative (ER-/PR-/Her2-) (21 vs. 12%, P = 0.26). A greater difference in the proportion of interval versus screen-detected tumors that were ER- (53 vs. 35%; P = 0.29), PR- (35 vs. 21%; P = 0.25) and EGFR+ (17 vs. 0%; P = 0.02) was evident among women over 50. There was a trend toward differential expression among women with familial risk for PR- (P = 0.005) and triple negative status (P = 0.02). This study provides new data indicating that EGFR may be important in the etiology of interval cancer and be a possible therapeutic target. Our data also suggest that biological differences between interval and screen-detected cancers are more defined in older women. Future studies to confirm this finding and to elucidate novel markers for characterizing interval cancers may be more beneficial to this subgroup.

Complementary approaches to assessing risk factors for interval breast cancer.

OBJECTIVE: To examine risk factors for interval breast cancer among women screened in a population-based mammography program. METHODS: Risk for interval cancer was assessed in terms of both the incidence per 10,000 negative screens and the proportion of all breast cancers diagnosed among screened women. Interval (N = 557) and screen-detected cancers (N = 1,545) were identified among 208,667 women receiving mammography in Colorado (1994-2001). Logistic regression was used to assess independent effects of multiple factors. RESULTS: Overall risk of interval cancer was 29.5/10,000 women screened. Incidence was higher in women >50 years (OR: 2.28, 1.86-2.80), with family history (OR: 2.23, 1.85-2.70), with dense breasts (OR: 3.84, 2.76-5.35), and using hormones (OR: 1.54, 1.20-1.97). Hispanics had lower incidence than Whites (OR: 0.52, 0.34-0.81). Interval cancers represented 26% of all cancers diagnosed. This proportion was higher in women <50 (OR: 1.41, 1.09-1.82) and in women with dense breasts (OR: 2.95, 1.94-4.48). CONCLUSIONS: Incidence of interval cancer increases with age, breast density, hormone use, and family history. Attempts to reduce occurrence of these cancers through more sensitive and/or intensive screening should focus on these subgroups. The disproportionate number of interval cancers associated with young age and dense breasts suggests these cancers result from both rapid growth and difficulties in detection.

The use of lacosamide in refractory status epilepticus.

BACKGROUND: Case reports suggest lacosamide may have a role in status epilepticus (SE). The purpose of this case series is to describe the use of lacosamide in refractory SE (RSE) at our institution. METHODS: Observational study of all patients admitted to the neurosciences intensive care unit with RSE who received at least one dose of lacosamide from October 2009 to September 2010. RESULTS: Nine patients received lacosamide after failure of at least two other agents. Lacosamide was started a median of 2 days (range: 0-14 days) after the onset of SE. The most frequently used dosing regimen was an initial intravenous dose of 200 mg followed by 200 mg every 12 h. Most patients had received 3 (range: 2-5) AEDs prior to lacosamide. Levetiracetam was used prior to lacosamide in all cases. No patients evaluated responded to lacosamide according to our predefined criteria. One patient developed angioedema after receiving two doses; another patient developed angioedema where timing in relation to the lacosamide was unclear. Care was withdrawn in three of the nine patients for reasons unrelated to lacosamide. Lacosamide was continued at discharge on all surviving patients except in one case of angioedema. CONCLUSIONS: This is the largest case series to date describing the use of lacosamide in patients with RSE. Despite the novel mechanism of action, we observed no evidence that lacosamide is effective in RSE; however, our sample size was small. Further study is needed to determine the role of lacosamide in SE, especially early in the treatment course.

Clinical Characteristics and Pharmacological Management of COVID-19 Vaccine-Induced Immune Thrombotic Thrombocytopenia With Cerebral Venous Sinus Thrombosis: A Review.

Importance: The COVID-19 pandemic saw one of the fastest developments of vaccines in an effort to combat an out-of-control pandemic. The 2 most common COVID-19 vaccine platforms currently in use, messenger RNA (mRNA) and adenovirus vector, were developed on the basis of previous research in use of this technology. Postauthorization surveillance of COVID-19 vaccines has identified safety signals, including unusual cases of thrombocytopenia with thrombosis reported in recipients of adenoviral vector vaccines. One of the devastating manifestations of this syndrome, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), is cerebral venous sinus thrombosis (CVST). This review summarizes the current evidence and indications regarding biology, clinical characteristics, and pharmacological management of VITT with CVST. Observations: VITT appears to be similar to heparin-induced thrombocytopenia (HIT), with both disorders associated with thrombocytopenia, thrombosis, and presence of autoantibodies to platelet factor 4 (PF4). Unlike VITT, HIT is triggered by recent exposure to heparin. Owing to similarities between these 2 conditions and lack of high-quality evidence, interim recommendations suggest avoiding heparin and heparin analogues in patients with VITT. Based on initial reports, female sex and age younger than 60 years were identified as possible risk factors for VITT. Treatment consists of therapeutic anticoagulation with nonheparin anticoagulants and prevention of formation of autoantibody-PF4 complexes, the latter being achieved by administration of high-dose intravenous immunoglobin (IVIG). Steroids, which can theoretically inhibit the production of new antibodies, have been used in combination with IVIG. In severe cases, plasma exchange should be used for clearing autoantibodies. Monoclonal antibodies, such as rituximab and eculizumab, can be considered when other therapies fail. Routine platelet transfusions, aspirin, and warfarin should be avoided because of the possibility of worsening thrombosis and magnifying bleeding risk. Conclusions and Relevance: Adverse events like VITT, while uncommon, have been described despite vaccination remaining the most essential component in the fight against the COVID-19 pandemic. While it seems logical to consider the use of types of vaccines (eg, mRNA-based administration) in individuals at high risk, treatment should consist of therapeutic anticoagulation mostly with nonheparin products and IVIG.

Expanded Access Programs, compassionate drug use, and Emergency Use Authorizations during the COVID-19 pandemic.

The US Food and Drug Administration (FDA) Expanded Access (EA) Program, which allows for compassionate uses of unapproved therapeutics and diagnostics outside of clinical trials, has gained significant traction during the Coronavirus 2019 (COVID-19) pandemic. While development of vaccines has been the major focus, uncertainties around new vaccine safety and effectiveness have spawned interest in other pharmacological options. Experimental drugs can also be approved under the FDA Emergency Use Authorization (EUA) program, designed to combat infectious disease and other threats. Here, we review the US experience in 2020 with pharmacological EA and EUA approvals during the pandemic. We also provide a description of, and clinical rationale for, each of the EA- or EUA-approved drugs (e.g. remdesivir, convalescent plasma, propofol 2%, hydroxychloroquine, ruxolitinib, bamlanivimab, baricitinib, casirivimab plus imdevimab) during the pandemic and concluding reflections on the EA program and its potential future uses.

Validity and reliability of an intuitive conscious sedation scoring tool: the nursing instrument for the communication of sedation.

OBJECTIVE: To develop a symmetrical 7-level scale (+3, "dangerously agitated" to -3, "deeply sedated") that is both intuitive and easy to use, the Nursing Instrument for the Communication of Sedation (NICS). DESIGN: Prospective cohort study. SETTING: University medical center. PATIENTS: Mixed surgical, medical intensive care unit (ICU) population. INTERVENTIONS: Patient assessment. MEASUREMENTS AND MAIN RESULTS: Criterion, construct, face validity, and interrater reliability of NICS over time and comparison of ease of use and nursing preference between NICS and four common intensive care unit sedation scales. A total of 395 observations were performed in 104 patients (20 intubated [INT], 84 non intubated) by 59 intensive care unit providers. Criterion validity was tested comparing NICS WITH the 8-point level of arousal scale, demonstrating excellent correlation (rs = .96 overall, .95 non intubated, 0.85 intubated, all p < .001). Construct validity was confirmed by comparing NICS with the Richmond Agitation-Sedation Scale, demonstrating excellent correlation (rs = .98, p < .001). Face validity was determined in a blinded survey of 53 intensive care unit nurses evaluating NICS and four other sedation scales. NICS was highly rated as easy to score, intuitive, and a clinically relevant measure of sedation, and agitation and was preferred overall (74% NICS, 17% Richmond Agitation-Sedation Scale, 11% Other, p < .001 NICS vs. Richmond Agitation-Sedation Scale). Interrater reliability was assessed, using the five scales at three timed intervals, during which 37% of patients received sedative medication. The mean NICS score consistently correlated with each of the other scales over time with an rs of >.9. Using the intraclass correlation coefficient as a measure of Interrater reliability, NICS scored as high, or higher than Richmond Agitation-Sedation Scale, Riker Sedation-Agitation Scale, Motor Activity Assessment Scale, or Ramsay over the three time periods. CONCLUSION: NICS is a valid and reliable sedation scale for use in a mixed population of intensive care unit patients. NICS ranked highest in nursing preference and ease of communication and may thus permit more effective and interactive management of sedation.

Contrast-Enhanced Mammography: A Scientific Review.

In this paper we provide an overview of contrast-enhanced mammography (CEM) and a review of the published literature in order to provide a picture of the current state of the evidence on the performance of CEM. Clinical research was fairly sparse following the demonstration of the technique in research subjects about 18 years ago, but the number of publications rapidly increased following commercialization 9 years ago, and even more so in the last 5 years. Initial studies compared CEM with mammography, and clearly showed that CEM could detect cancers not visible on mammography. More recent studies have primarily focused on comparing the performance of CEM with contrast-enhanced magnetic resonance imaging (MRI) in selected cohorts. These studies have almost uniformly shown CEM and MRI to have similar sensitivities, with sensitivity and accuracy showing more variability from study to study. With increasing clinical use, a large number of retrospective reviews of CEM have appeared, showing utility of CEM in the diagnostic clinical setting. Most recently, a small number of papers have been published looking at CEM for high-risk and dense breast screening, two potentially large applications of the technique, showing it to outperform mammography in both populations. CEM has clearly been shown to have clinical utility, but more prospective studies, including screening studies, are needed to further evaluate its performance, especially in comparison with MRI.