Low value of inherited thrombophilia testing among patients with stroke or transient ischemic attack: A three-year retrospective study.

BACKGROUND/PURPOSE: Inherited thrombophilia testing in the acute inpatient setting is controversial and expensive, and rarely changes clinical management. We evaluated ordering patterns and results of inpatient inherited thrombophilia testing for patients who presented with an isolated acute ischemic stroke or transient ischemic attack (TIA) without concurrent venous thromboembolism. METHODS: We retrospectively analyzed patients admitted for acute ischemic stroke or TIA between January 1st, 2019 and December 31st, 2021 at Thomas Jefferson University Hospitals in Philadelphia, PA and who underwent inherited thrombophilia testing during the hospital admission. Charts were reviewed to determine stroke risk factors, test results, and clinical management. RESULTS: Among 2108 patients admitted for acute ischemic stroke or TIA (including branch and central retinal artery occlusions) during the study period, the study included 249 patients (median age 49.0 years, 50.2% female) who underwent inpatient testing for factor V Leiden, prothrombin G20210A variant, hyperhomocysteinemia, PAI-1 elevation, and deficiencies of protein C and S and antithrombin. 42.2% of patients had at least one abnormal test, and among the 1035 tests ordered, 14.3% resulted abnormal. However, 28% of abnormal tests were borderline positive antigen or activity assays that likely represented false positives. There was no significant difference in the likelihood of a positive test among patients without stroke risk factors vs those with risk factors (47.1% vs 40.9%, P = .428), nor any significant difference between those under vs over age 50 years (45.7% vs 38.3%, P = .237). No patients with an abnormal result had their clinical management changed as a result. Charges for the tests totaled $468,588 USD. CONCLUSIONS: Inherited thrombophilia testing in the hospital immediately following isolated acute arterial ischemic stroke or TIA was associated with high rates of likely false positive results and was expensive. Positive results did not change clinical management in a single case.

Unruptured Cerebral Aneurysms: Evaluation and Management.

The evolution of imaging techniques and their increased use in clinical practice have led to a higher detection rate of unruptured intracranial aneurysms. The diagnosis of an unruptured intracranial aneurysm is a source of significant stress to the patient because of the concerns for aneurysmal rupture, which is associated with substantial rates of morbidity and mortality. Therefore, it is important that decisions regarding optimum management are made based on the comparison of the risk of aneurysmal rupture with the risk associated with intervention. This review provides a comprehensive overview of the epidemiology, pathophysiology, natural history, clinical presentation, diagnosis, and management options for unruptured intracranial aneurysms based on the current evidence in the literature. Furthermore, the authors discuss the genetic abnormalities associated with intracranial aneurysm and current guidelines for screening in patients with a family history of intracranial aneurysms. Since there is significant controversy in the optimum management of small unruptured intracranial aneurysms, we provided a systematic approach to their management based on patient and aneurysm characteristics as well as the risks and benefits of intervention.

Association between hyperoxia and mortality after stroke: a multicenter cohort study.

OBJECTIVE: To test the hypothesis that hyperoxia was associated with higher in-hospital mortality in ventilated stroke patients admitted to the ICU. DESIGN: Retrospective multicenter cohort study. SETTING: Primary admissions of ventilated stroke patients with acute ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage who had arterial blood gases within 24 hours of admission to the ICU at 84 U.S. ICUs between 2003 and 2008. Patients were divided into three exposure groups: hyperoxia was defined as PaO2 ≥ 300 mm Hg (39.99 kPa), hypoxia as any PaO2<60 mm Hg (7.99 kPa) or PaO2/FiO2 ratio ≤ 300, and normoxia, not defined as hyperoxia or hypoxia. The primary outcome was in-hospital mortality. PARTICIPANTS: Two thousand eight hundred ninety-four patients. METHODS: Patients were divided into three exposure groups: hyperoxia was defined as PaO2 more than or equal to 300 mm Hg (39.99 kPa), hypoxia as any PaO2 less than 60 mm Hg (7.99 kPa) or PaO2/FIO2 ratio less than or equal to 300, and normoxia, not defined as hyperoxia or hypoxia. The primary outcome was in-hospital mortality. INTERVENTIONS: Exposure to hyperoxia. RESULTS: Over the 5-year period, we identified 554 ventilated patients with acute ischemic stroke (19%), 936 ventilated patients with subarachnoid hemorrhage (32%), and 1,404 ventilated patients with intracerebral hemorrhage (49%) of whom 1,084 (38%) were normoxic, 1,316 (46%) were hypoxic, and 450 (16%) were hyperoxic. Mortality was higher in the hyperoxia group as compared with normoxia (crude odds ratio 1.7 [95% CI 1.3-2.1]; p < 0.0001) and hypoxia groups (crude odds ratio, 1.3 [95% CI, 1.1-1.7]; p < 0.01). In a multivariable analysis adjusted for admission diagnosis, other potential confounders, the probability of being exposed to hyperoxia, and hospital-specific effects, exposure to hyperoxia was independently associated with in-hospital mortality (adjusted odds ratio, 1.2 [95% CI, 1.04-1.5]). CONCLUSION: In ventilated stroke patients admitted to the ICU, arterial hyperoxia was independently associated with in-hospital death as compared with either normoxia or hypoxia. These data underscore the need for studies of controlled reoxygenation in ventilated critically ill stroke populations. In the absence of results from clinical trials, unnecessary oxygen delivery should be avoided in ventilated stroke patients.

The prevalence and impact of mortality of the acute respiratory distress syndrome on admissions of patients with ischemic stroke in the United States.

PURPOSE: To determine the epidemiology of the acute respiratory distress syndrome (ARDS) and impact on in-hospital mortality in admissions of patients with acute ischemic stroke (AIS) in the United States. METHODS: Retrospective cohort study of admissions with a diagnosis of AIS and ARDS from 1994 to 2008 identified through the Nationwide Inpatient Sample. RESULTS: During the 15-year study period, we found 55 58 091 admissions of patients with AIS. The prevalence of ARDS in admissions of patients with AIS increased from 3% in 1994 to 4% in 2008 (P < .001). The ARDS was more common among younger men, nonwhites, and associated with history of congestive heart failure, hypertension, chronic obstructive pulmonary disease, renal failure, chronic liver disease, systemic tissue plasminogen activator, craniotomy, angioplasty or stent, sepsis, and multiorgan failures. Mortality due to AIS and ARDS decreased from 8% in 1994 to 6% in 2008 (P < .001) and 55% in 1994 to 45% in 2008 (P < .001), respectively. The ARDS in AIS increased in-hospital mortality (odds ratio, 14; 95% confidence interval, 13.5-14.3). A significantly higher length of stay was seen in admissions of patients with AIS having ARDS. CONCLUSION: Our analysis demonstrates that ARDS is rare after AIS. Despite an overall significant reduction in mortality after AIS, ARDS carries a higher risk of death in this patient population.

Red blood cell transfusion increases the risk of thrombotic events in patients with subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Red blood cell transfusion (RBCT) may increase the risk of thrombotic events (TE) in patients with subarachnoid hemorrhage (SAH) through changes induced by storage coupled with SAH-related hypercoagulability. We sought to investigate the association between RBCT and the risk of TE in patients with SAH. METHODS: 205 consecutive patients with acute, aneurysmal SAH admitted to the neurovascular intensive care unit of a tertiary care, academic medical center between 3/2008 and 7/2009 were enrolled in a retrospective, observational cohort study. TE were defined as the composite of venous thromboembolism (VTE), myocardial infarction (MI), and cerebral infarction noted on brain CT scan. Secondary endpoints included the risk of VTE, poor outcome (modified Rankin score 3-6 at discharge), and in-hospital mortality. RESULTS: 86/205 (42 %) received RBCT. Eighty-eight (43 %) had a thrombotic complication. Forty (34 %) of 119 non-transfused and 48/86 (56 %) transfused patients had a TE (p = 0.002). In multivariate analysis, RBCT was associated with more TE by [OR 2.4; 95 % CI (1.2, 4.6); p = 0.01], VTE [OR 2.3; 95 % CI (1.0, 5.2); p = 0.04], and poor outcome [OR 5.0; 95 % CI (1.9, 12.8); p < 0.01]. The risk of TE increased by 55 % per unit transfused when controlling for univariate variables. Neither mean nor maximum age of blood was significantly associated with thrombotic risk. CONCLUSIONS: RBCT is associated with an increased risk of TE and VTE in SAH patients. A dose-dependent relationship exists between number of units transfused and thrombosis. Age of blood does not appear to play a role.

Cerebral arteriovenous malformations: evaluation and management.

There has been increased detection of incidental AVMs as result of the frequent use of advanced imaging techniques. The natural history of AVM is poorly understood and its management is controversial. This review provides an overview of the epidemiology, pathophysiology, natural history, clinical presentation, diagnosis, and management of AVMs. The authors discussed the imaging techniques available for detecting AVMs with regard to the advantages and disadvantages of each imaging modality. Furthermore, this review paper discusses the factors that must be considered for the most appropriate management strategy (based on the current evidence in the literature) and the risks and benefits of each management option.

Hospital mortality in primary admissions of septic patients with status epilepticus in the United States*.

OBJECTIVE: To determine the prevalence of status epilepticus, associated factors, and relationship with in-hospital mortality in primary admissions of septic patients in the United States. DESIGN: Cross-sectional study. SETTING: Primary admissions of adult patients more than 18 years old with a diagnosis of sepsis and status epilepticus from 1988 to 2008 identified through the Nationwide Inpatient Sample. PARTICIPANTS: A total of 7,669,125 primary admissions of patients with sepsis. INTERVENTIONS: None. RESULTS: During the 21-year study period, the prevalence of status epilepticus in primary admissions of septic patients increased from 0.1% in 1988 to 0.2% in 2008 (p < 0.001). Status epilepticus was also more common among later years, younger admissions, female gender, Black race, rural hospital admissions, and in those patients with organ dysfunctions. Mortality of primary sepsis admissions decreased from 20% in 1988 to 18% in 2008 (p < 0.001). Mortality in status epilepticus during sepsis decreased from 43% in 1988 to 28% in 2008. In-hospital mortality after admissions for sepsis was associated with status epilepticus, older age, and Black and Native American/Eskimo race; patients admitted to a rural or urban private hospitals; and patients with organ dysfunctions. CONCLUSION: Our analysis demonstrates that status epilepticus after admission for sepsis in the United States was rare. Despite an overall significant reduction in mortality after admission for sepsis, status epilepticus carried a higher risk of death. More aggressive electrophysiological monitoring and a high level of suspicion for the diagnosis of status epilepticus may be indicated in those patients with central nervous system organ dysfunction after sepsis.

Treatment of status epilepticus: an international survey of experts.

BACKGROUND: As part of the development of the Neurocritical Care Society (NCS) Status Epilepticus (SE) Guidelines, the NCS SE Writing Committee conducted an international survey of SE experts. METHODS: The survey consisted of three patient vignettes (case 1, an adult; case 2, an adolescent; case 3, a child) and questions regarding treatment. The questions for each case focused on initial and sequential therapy as well as when to use continuous intravenous (cIV) therapy and for what duration. Responses were obtained from 60/120 (50%) of those surveyed. RESULTS: This survey reveals that there is expert consensus for using intravenous lorazepam for the emergent (first-line) therapy of SE in children and adults. For urgent (second-line) therapy, the most common agents chosen were phenytoin/fosphenytoin, valproate sodium, and levetiracetam; these choices varied by the patient age in the case scenarios. Physicians who care for adult patients chose cIV therapy for RSE, especially midazolam and propofol, rather than a standard AED sooner than those who care for children; and in children, there is a reluctance to choose propofol. Pentobarbital was chosen later in the therapy for all ages. CONCLUSION: There is close agreement between the recently published NCS guideline for SE and this survey of experts in the treatment of SE.

Guidelines for the evaluation and management of status epilepticus.

Status epilepticus (SE) treatment strategies vary substantially from one institution to another due to the lack of data to support one treatment over another. To provide guidance for the acute treatment of SE in critically ill patients, the Neurocritical Care Society organized a writing committee to evaluate the literature and develop an evidence-based and expert consensus practice guideline. Literature searches were conducted using PubMed and studies meeting the criteria established by the writing committee were evaluated. Recommendations were developed based on the literature using standardized assessment methods from the American Heart Association and Grading of Recommendations Assessment, Development, and Evaluation systems, as well as expert opinion when sufficient data were lacking.

Intravenous thrombolysis in the elderly is facilitated by a tele-stroke network: A cross-sectional study.

BACKGROUND: Data suggest that elderly patients have less favorable outcomes after ischemic stroke. OBJECTIVE: To study the outcomes after intravenous tissue plasminogen activator (tPA) administration in elderly patients with acute ischemic stroke. METHODS: Cross-sectional study using prospective collected patient data maintained via our "tele-stroke" network, which provides acute care in 29 community hospitals within our region from 2013-2015. Exposure of interest was age divided into >80 years (octogenarian) or younger. Outcomes of interest were rate of intravenous tPA administration, hemorrhagic transformation (ICH), in-hospital neurological deterioration, and poor outcome defined as a composite of hospital discharge to long-term care facility or death. RESULTS: Mean age 67 ± 16 years, 57 % (743/1317) were women, and median (Md) NIHSS was 4 (Interquartile Range [IQR] 8). The rate of tPA was 20 % (267/1317). Compared to reported rates of tPA administration in the nation, our tPA rate exceeded the one from the literature (20 % v 3%, z = 2.83, SE = 0.04, p = .005). There were no differences in ICH or neurological deterioration. The octogenarian group had a higher proportion of poor-outcome (61 % vs. 23 %, p < 0.001) than the younger group but similar in-hospital case-fatality (25 % v 14 %, p = 0.09). Predictors of poor-outcome were age >80 (OR 4.9; CI, 2.0-12, p < .001) and α-NIHSS>9. (OR 8.7; CI, 3.5-20, p < .001). CONCLUSION: Our data suggest that in our "tele-stroke" network, rates of tPA administration are higher than those reported in the literature and that this rate was not different in octogenarians compared to younger patients. Octogenarians were not at risk for ICH or neurological deterioration after tPA administration. However, octogenarians had a higher risk of poor outcome.

Beyond intravenous thrombolysis.

The National Institute of Neurological Disorders and Stroke trial of recombinant tissue plasminogen activator has been considered a landmark study in the acute treatment of ischemic stroke. Unfortunately, only a small percentage of all ischemic stroke patients presents to the hospital in time to receive the drug. Moreover, the recannalization rate of a major artery occlusion, such as the proximal middle cerebral artery or top of the internal carotid artery occlusion, after intravenous (IV) thrombolytic therapy has been disappointingly low. Since the Food and Drug Administration's approval of IV plasminogen activator, there have been numerous randomized clinical trials investigating the safety and efficacy of different thrombolytics administered in various time frames. In addition to the IV administration, efforts have been made in order to study the radiographic as well as clinical effects of intra-arterial (IA) thrombolysis. The combination of IV and IA thrombolysis has been studied. For patients who do not qualify for receiving chemical thrombolysis, new devices have been developed for mechanical thrombectomy. Angioplasty and stenting procedures are being performed more frequently than in the past as one of the treatment modalities for acute ischemic stroke patients. Relentless research effort is being made internationally in order to fight the devastating disease which now goes beyond the conventional IV thrombolysis.

Herpes Simplex Viral Encephalitis Masquerading as a Classic Left MCA Stroke.

Objective. Stroke is a clinical diagnosis, with a history and physical examination significant for acute onset focal neurological symptoms and signs, often occurring in patients with known vascular risk factors and is frequently confirmed radiographically. Case Report. A 79-year-old right-handed woman, with a past medical history of hypertension, hyperlipidemia, and prior transient ischemic attack (TIA), presented with acute onset global aphasia and right hemiparesis, in the absence of fever or prodrome. This was initially diagnosed as a proximal left middle cerebral artery (MCA) stroke. However, CT perfusion failed to show evidence of reduced blood volume, and CT angiogram did not show evidence of a proximal vessel occlusion. Furthermore, MRI brain did not demonstrate any areas of restricted diffusion. EEG demonstrated left temporal periodic lateralized epileptiform discharges (PLEDs). The patient was empirically loaded with a bolus valproic acid and started on acyclovir, both intravenously. CSF examination demonstrated a pleocytosis and PCR confirmed the diagnosis of herpes simplex viral encephalitis (HSVE). Conclusions. HSVE classically presents in a nonspecific fashion with fever, headache, and altered mental status. However, acute focal neurological signs, mimicking stroke, are possible. A high degree of suspicion is required to institute appropriate therapy and decrease morbidity and mortality associated with HSVE.

Pennsylvania comprehensive stroke center collaborative: Statement on the recently updated IV rt-PA prescriber information for acute ischemic stroke.

OBJECTIVE: Recently, the FDA guidelines regarding the eligibility of patients with acute ischemic stroke to receive IV rt-PA have been modified and are not in complete accord with the latest AHA/ASA guidelines. The resultant differences may result in discrepancies in patient selection for intravenous thrombolysis. METHODS: Several comprehensive stroke centers in the state of Pennsylvania have undertaken a collaborative effort to clarify and unify our own recommendations regarding how to reconcile these different guidelines. RESULTS: Seizure at onset of stroke, small previous strokes that are subacute or chronic, multilobar infarct involving more than one third of the middle cerebral artery territory on CT scan, hypoglycemia, minor or rapidly improving symptoms should not be considered as contraindications for intravenous thrombolysis. It is recommended to follow the AHA/ASA guidelines regarding blood pressure management and bleeding diathesis. Patients receiving factor Xa inhibitors and direct thrombin inhibitors within the preceding 48 h should be excluded from receiving IV rt-PA. CT angiography is effective in identifying candidates for endovascular therapy. Consultation with and/or transfer to a comprehensive stroke center should be an option where indicated. Patients should receive IV rt-PA up to 4.5h after the onset of stroke. CONCLUSIONS: The process of identifying patients who will benefit the most from IV rt-PA is still evolving. Considering the rapidity with which patients need to be evaluated and treated, it remains imperative that systems of care adopt protocols to quickly gather the necessary data and have access to expert consultation as necessary to facilitate best practices.

Novel partial anomalous pulmonary venous connection associated with brain abscess.

BACKGROUND: Right-to-left vascular shunts are associated with brain abscess. CASE REPORT: We present a 47-year-old female with a cryptogenic left thalamic abscess on which Streptococcus mitis grew upon aspiration. Computed tomography of the chest with contrast agent revealed an anomalous connection between the left superior pulmonary and brachiocephalic veins. A right-to-left shunt was confirmed in a transthoracic echocardiogram study in which bubbles were injected into the left arm; this shunt had not previously been noted upon right-arm injection. CONCLUSIONS: We recommend aggressive evaluation for right-to-left shunts in patients who present with cryptogenic brain abscesses. In addition to imaging, this should include a bubble-based study with left-arm saline injection.

Targeted temperature management after intracerebral hemorrhage (TTM-ICH): methodology of a prospective randomized clinical trial.

RATIONALE: Intracerebral hemorrhage causes 15% of strokes annually in the United States, and there is currently no effective therapy. AIMS AND HYPOTHESIS: This is a clinical trial designed to study the safety, feasibility, and efficacy of a protocol of targeted temperature management to moderate hypothermia in intracerebral hemorrhage patients. METHODS: The targeted temperature management after intracerebral hemorrhage trial is a prospective, single-center, interventional, randomized, parallel, two-arm (1:1) phase-II clinical trial with blinded end-point ascertainment. Intracerebral hemorrhage patients will be randomized within 18 h of symptom onset to either 72 h of targeted temperature management to moderate hypothermia (32-34°C) followed by a controlled rewarming at of 0·05-0·1°C per hour or 72 h of targeted temperature management to normothermia (36-37°C) using endovascular or surface cooling. OUTCOMES: The primary outcome is the development of serious adverse events possibly and probably related to treatment. Secondary outcomes include in-hospital neurological deterioration between day 0-7, in-hospital mortality, functional outcome measured by the modified Rankin scale at discharge and 90 days, and effect of treatment allocation on cerebral edema and hematoma volume. DISCUSSION: Intracerebral hemorrhage remains the most severe form of stroke with limited options to improve survival. As the early resuscitation phase in the intensive care unit represents the greatest opportunity for impact on clinical outcome, it also appears to be the most promising window of opportunity to demonstrate a benefit when investigating aggressive treatments. CONCLUSION: More research of novel therapies to improve outcomes after intracerebral hemorrhage is desperately needed. The results of the targeted temperature management after intracerebral hemorrhage clinical trial may provide additional information on the applicability of targeted temperature management after intracerebral hemorrhage.

The epidemiology, risk factors, and impact on hospital mortality of status epilepticus after subdural hematoma in the United States.

INTRODUCTION: Subdural hematoma (SDH) is a well described risk factor in the development of Status Epilepticus (SE), however the epidemiology of SE after SDH is unknown. In this study, we sought to determine the epidemiology of SE, the prevalence of risk factors, and impact on hospital mortality using a large administrative dataset. METHODS: Data was derived from the Nationwide Inpatient Sample from 1988 through 2011. We queried the NIS database for patients older than 18 years, with a diagnosis of SDH and SE. Diagnoses were defined by ICD 9 CM codes 432.1, 852.2, 852.3 and 345.3 for SE. Adjusted incidence rates of admission and prevalence proportions were calculated. Multivariate logistic models were then fitted to assess for the impact of status epilepticus on hospital mortality. RESULTS: Over the 23-year period, we identified more than 1,583,255 admissions with a diagnosis of SDH. The prevalence of SE in this cohort was 0.5% (7,421 admissions). The population adjusted incidence rate of admissions of SDH increased from 13/100,000 in 1988 to 38/100,000 in 2011. The prevalence of SE in SDH, increased from 0.5% in 1988 to 0.7% in 2011. In hospital mortality of patients with SDH and without SE decreased from 17.9% to 10.3% while in hospital mortality of patients with SDH and SE did not statistically change. Mortality increased over the same period (2.3/100,000 in 1988 to 3.9/100.000 in 2011) and the diagnosis of SE increased mortality in this cohort (OR 2.17, p < 0.0001). The risk of SE remained stable throughout the study period, but was higher among older patients, blacks, and in those with respiratory, metabolic, hematological, and renal system dysfunction. CONCLUSION: Our study demonstrates that the incidence of admissions of SDH is increasing in the United States. Despite a decline in the overall SDH related mortality, SE increased the risk of in-hospital death in patients with a primary diagnosis of SDH.

The incidence and risk factors of associated acute myocardial infarction (AMI) in acute cerebral ischemic (ACI) events in the United States.

OBJECTIVES: To determine the association between myocardial infarction (AMI) and clinical outcome in patients with primary admissions diagnosis of acute cerebral ischemia (ACI) in the US. METHODS: Data from Nationwide Inpatient Sample (NIS) was queried from 2002-2011 for inpatient admissions of patients with a primary diagnosis of ACI with and without AMI using International Classification of Diseases, Ninth Revision, Clinical Modification coding (ICD-9). A multivariate stepwise regression analysis was performed to assess the correlation between identifiable risk factors and clinical outcomes. RESULTS: During 10 years the NIS recorded 886,094 ACI admissions with 17,526 diagnoses of AMI (1.98%). The overall cumulative mortality of cohort was 5.65%. In-hospital mortality was associated with AMI (aOR 3.68; 95% CI 3.49-3.88, p≤0.0001), rTPA administration (aOR 2.39 CI, 2.11-2.71, p<0.0001), older age (aOR 1.03, 95% CI, 1.03-1.03, P<0.0001) and women (aOR 1.06, 95% CI 1.03-1.08, P<0.0001). Overall, mortality risk declined over the course of study; from 20.46% in 2002 to 11.8% in 2011 (OR 0.96, 95% CI 0.95-0.96, P<0.0001). Survival analysis demonstrated divergence between the AMI and non-AMI sub-groups over the course of study (log-rank p<0.0001). CONCLUSION: Our study demonstrates that although the prevalence of AMI in patients hospitalized with primary diagnosis of ACI is low, it negatively impacts survival. Considering the high clinical burden of AMI on mortality of ACI patients, a high quality monitoring in the event of cardiac events should be maintained in this patient cohort. Whether prompt diagnosis and treatment of associated cardiovascular diseases may improve outcome, deserves further study.

A rationally designed form of the TLR5 agonist, flagellin, supports superior immunogenicity of Influenza B globular head vaccines.

Previously, we demonstrated that for H1N1 and H5N1 influenza strains, the globular head of the hemagglutinin (HA) antigen fused to flagellin of Salmonella typhimurium fljB (STF2) is highly immunogenic in preclinical models and man (Song et al. (2008) [13]; Song et al. (2009) [14]; Taylor et al. (2012) [12]). Further we showed that the vaccine format, or point of attachment of the vaccine antigen to flagellin, can dramatically affect the immunogenicity and safety profile of the vaccine. However, Influenza B vaccines based on these formats are poor triggers of TLR5 and consequently are poorly immunogenic. Through rational design, here we show that we have identified a fusion position within domain 3 of flagellin that improves TLR5 signaling and consequently, immunogenicity of multiple influenza B vaccines. Our results demonstrate that, similar to influenza A strains, the protective subunit of the influenza B HA can be fused to flagellin and produced in a standard prokaryotic expression system thereby allowing for cost and time efficient production of multivalent seasonal influenza vaccines.

Secondary membranous nephropathy associated with guillain-barré syndrome.

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome (NS) in adults. It may be primary, usually mediated by IgG4 anti-phospholipase A2 autoantibodies or secondary to various other conditions. Guillain- Barré syndrome (GBS) has been associated with MN, but a cause and effect relation has not been proven. We present a case of concurrent development of GBS and severe NS, with renal biopsy demonstrating MN. IgG4 stain was negative, indicating that most likely, the MN was secondary and probably caused by the underlying GBS.