H3K27me3 Demethylase UTX Restrains Plasma Cell Formation.

B cell differentiation is associated with substantial transcriptional, metabolic, and epigenetic remodeling, including redistribution of histone 3 lysine 27 trimethylation (H3K27me3), which is associated with a repressive chromatin state and gene silencing. Although the role of the methyltransferase EZH2 (Enhancer of zeste homolog 2) in B cell fate decisions has been well established, it is not known whether H3K27me3 demethylation is equally important. In this study, we showed that simultaneous genetic deletion of the two H3K27 demethylases UTX and JMJD3 (double-knockout [Utx fl/fl Jmjd3 fl/fl Cd19 cre/+] [dKO]) led to a significant increase in plasma cell (PC) formation after stimulation with the T cell-independent Ags LPS and NP-Ficoll. This phenotype occurred in a UTX-dependent manner as UTX single-knockout mice, but not JMJD3 single-knockout mice, mimicked the dKO. Although UTX- and JMJD3-deficient marginal zone B cells showed increased proliferation, dKO follicular B cells also showed increased PC formation. PCs from dKO mice upregulated genes associated with oxidative phosphorylation and exhibited increased spare respiratory capacity. Mechanistically, deletion of Utx and Jmjd3 resulted in higher levels of H3K27me3 at proapoptotic genes and resulted in reduced apoptosis of dKO PCs in vivo. Furthermore, UTX regulated chromatin accessibility at regions containing ETS and IFN regulatory factor (IRF) transcription factor family motifs, including motifs of known repressors of PC fate. Taken together, these data demonstrate that the H3K27me3 demethylases restrain B cell differentiation.

Web-Based Health Information Seeking by People Living With Multiple Sclerosis: Qualitative Investigation of the Multiple Sclerosis Online Course.

BACKGROUND: Digital technologies have afforded people living with multiple sclerosis (MS) access to telehealth consultations, diagnostic tools, and monitoring. Although health care professionals remain the most trusted source of information, the internet has emerged as a valuable resource for providing MS-related information, particularly during the COVID-19 pandemic. Notably, people living with MS are increasingly seeking educational content for a range of topics related to the self-management of MS; however, web-based information seeking remains largely underevaluated. To address this gap and ensure that web-based health-related information is accessible and engaging, this study used qualitative methods to analyze the reflections from participants of web-based educational programs for people living with MS. OBJECTIVE: This study aimed to explore the motivations, behaviors, and expectations of web-based health information seeking for people living with MS. METHODS: We conducted semistructured interviews for 38 people living with MS 1 month after they completed the novel MS Online Course, which provided information on modifiable lifestyle-related risk factors for people living with MS. Of the 38 participants, 22 (58%) completed the intervention course and 16 (42%) completed the standard care course. Inductive thematic analysis was used within a qualitative paradigm, and 2 authors coded each interview separately and arrived at themes with consensus. RESULTS: We identified 2 themes: motivation to learn and MS information on the web. The diagnosis of MS was described as a pivotal moment for precipitating web-based information seeking. People living with MS sought lifestyle-related information to facilitate self-management and increase control of their MS. Although social media sites and MS websites were considered useful for providing both support and information, discretion was needed to critically appraise information. Recognizable institutions were frequently accessed because of their trustworthiness. CONCLUSIONS: This study provided novel insights into the motivations of people living with MS for seeking web-based health information. Furthermore, their preferences for the content and format of the web-based information accessed and their experiences and reactions to this information were explored. These findings may guide educators, researchers, and clinicians involved in MS care to optimize the engagement and processing of web-based health information seeking by people living with MS.

Implementing DASH-aligned Congregate Meals and Self-Measured Blood Pressure in two senior centers: An open label study.

BACKGROUND AND AIMS: Cardiovascular Disease (CVD) poses significant health risks for seniors, especially among low-income and minority communities. Senior centers offer multiple services. We tested whether implementing two evidence-based interventions- DASH-aligned meals provided through an existing congregate meal program, and support for home Self-Measured Blood Pressure (SMBP) monitoring-lowers blood pressure among participants at two senior centers serving low-income, racially diverse communities. METHODS AND RESULTS: Open-label study, enrolling clients aged ≥60, eating ≥4 meals/week at two NYC senior centers. Participants received DASH-aligned congregate meals, and training in nutrition, BP management education, and personal SMBP device. Co-Primary outcomes: a) change in systolic BP measured by independent health professionals, and b) change in percent with "controlled BP" (Eighth Joint National Committee (JNC-8) Guidelines), at Month 1 compared to Baseline. SECONDARY OUTCOMES: Changes in BP at Months 3 and 5/6 (last measure). We enrolled 94 participants; COVID closures interrupted implementation mid-study. Mean systolic BP at Month-1 changed by -4.41 mmHg (n = 61 p = 0.07) compared to Baseline. Participants with controlled BP increased (15.7%) at Month 1. Change in mean BP at Month 1 was significantly correlated with BMI (p = 0.02), age (p = 0.04), and baseline BP (p < 0.001). Mean systolic SMBP changed by -6.9 mmHg (p = 0.004) at Months 5/6. CONCLUSIONS: Implementing an evidence-based multi-component BP-lowering intervention within existing congregate meal programs at senior centers serving minority and low-income communities is feasible, and early findings show promising evidence of effectiveness. This approach to cardiovascular risk reduction should be further tested for widespread adoption and impact. Registered on ClinicalTrials.gov NCT03993808 (June 21st, 2019).

No evidence of false-negative Plasmodium falciparum rapid diagnostic results in Monrovia, Liberia.

BACKGROUND: Malaria diagnosis in many malaria-endemic countries relies mainly on the use of rapid diagnostic tests (RDTs). The majority of commercial RDTs used in Africa detect the Plasmodium falciparum histidine-rich protein 2 (PfHRP2). pfhrp2/3 gene deletions can therefore lead to false-negative RDT results. This study aimed to evaluate the frequency of PCR-confirmed, false-negative P. falciparum RDT results in Monrovia, Liberia. METHODS: PfHRP2-based RDT (Paracheck Pf®) and microscopy results from 1038 individuals with fever or history of fever (n = 951) and pregnant women at first antenatal care (ANC) visit (n = 87) enrolled in the Saint Joseph's Catholic Hospital (Monrovia) from March to July 2019 were used to assess the frequency of false-negative RDT results. True-false negatives were confirmed by detecting the presence of P. falciparum DNA by quantitative PCR in samples from individuals with discrepant RDT and microscopy results. Samples that were positive by 18S rRNA qPCR but negative by PfHRP2-RDT were subjected to multiplex qPCR assay for detection of pfhrp2 and pfhrp3. RESULTS: One-hundred and eighty-six (19.6%) and 200 (21.0%) of the 951 febrile participants had a P. falciparum-positive result by RDT and microscopy, respectively. Positivity rate increased with age and the reporting of joint pain, chills and shivers, vomiting and weakness, and decreased with the presence of coughs and nausea. The positivity rate at first ANC visit was 5.7% (n = 5) and 8% (n = 7) by RDT and microscopy, respectively. Out of 207 Plasmodium infections detected by microscopy, 22 (11%) were negative by RDT. qPCR confirmed absence of P. falciparum DNA in the 16 RDT-negative but microscopy-positive samples which were available for molecular testing. Among the 14 samples that were positive by qPCR but negative by RDT and microscopy, 3 only amplified pfldh, and among these 3 all were positive for pfhrp2 and pfhrp3. CONCLUSION: There is no qPCR-confirmed evidence of false-negative RDT results due to pfhrp2/pfhrp3 deletions in this study conducted in Monrovia (Liberia). This indicates that these deletions are not expected to affect the performance of PfHRP2-based RDTs for the diagnosis of malaria in Liberia. Nevertheless, active surveillance for the emergence of PfHRP2 deletions is required.

Pituitary apoplexy and panhypopituitarism following acute leptospirosis.

Leptospirosis is a common tropical febrile illness which may manifest with the hepatorenal syndrome and systemic hemorrhagic manifestations. Pituitary apoplexy is a rare but life-threatening condition characterized by a hemorrhage within the pituitary gland or a pituitary adenoma. Apoplexy is very rarely associated with some inducing events such as infectious diseases such as dengue hemorrhagic fever, Hantaan virus, Puumala virus have also been reported to cause pituitary apoplexy. We present the first case of pituitary apoplexy in a patient who was being treated for leptospirosis and discuss the possible mechanisms of apoplexy in the scenario presented. We also review other reports of infectious causes that may result in pituitary apoplexy.

Unintended consequences of changes to lung allocation policy.

Organ allocation for transplantation aims to balance the principles of justice and medical utility to optimally utilize a scarce resource. To address practical considerations, the United States is divided into 58 donor service areas (DSA), each constituting the first unit of allocation. In November 2017, in response to a lawsuit in New York, an emergency action change to lung allocation policy replaced the DSA level of allocation for donor lungs with a 250 nautical mile circle around the donor hospital. Similar policy changes are being implemented for other organs including heart and liver. Findings from a recent US Department of Health and Human Services report, supplemented with data from our institution, suggest that the emergency policy has not resulted in a change in the type of patients undergoing lung transplantation (LT) or early postoperative outcomes. However, there has been a significant decline in local LT, where donor and recipient are in the same DSA. With procurement teams having to travel greater distances, organ ischemic time has increased and median organ cost has more than doubled. We propose potential solutions for consideration at this critical juncture in the field of transplantation. Policymakers should choose equitable and sustainable access for this lifesaving discipline.

LptE binds to and alters the physical state of LPS to catalyze its assembly at the cell surface.

The assembly of lipopolysaccharide (LPS) on the surface of Gram-negative bacterial cells is essential for their viability and is achieved by the seven-protein LPS transport (Lpt) pathway. The outer membrane (OM) lipoprotein LptE and the ß-barrel membrane protein LptD form a complex that assembles LPS into the outer leaflet of the OM. We report a crystal structure of the Escherichia coli OM lipoprotein LptE at 2.34 Å. The structure reveals homology to eukaryotic LPS-binding proteins and allowed for the prediction of an LPS-binding site, which was confirmed by genetic and biophysical experiments. Specific point mutations at this site lead to defects in OM biogenesis. We show that wild-type LptE disrupts LPS-LPS interactions in vitro and that these mutations decrease the ability of LptE to disaggregate LPS. Transmission electron microscopic imaging shows that LptE can disrupt LPS aggregates even at substoichiometric concentrations. We propose a model in which LptE functions as an LPS transfer protein in the OM translocon by disaggregating LPS during transport to allow for its insertion into the OM.

A Model for Predicting Persistent Elevation of Factor VIII among Patients with Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Elevated levels of coagulation factor VIII (FVIII) may persist independent of the acute-phase response; however, this relationship has not been investigated relative to acute ischemic stroke (AIS). We examined the frequency and predictors of persistently elevated FVIII in AIS patients. METHODS: AIS patients admitted between July 2008 and May 2014 with elevated baseline FVIII levels and repeat FVIII levels drawn for more than 7 days postdischarge were included. The patients were dichotomized by repeat FVIII level for univariate analysis at 150% and 200% activity thresholds. An adjusted model was developed to predict the likelihood of persistently elevated FVIII levels. RESULTS: Among 1616 AIS cases, 98 patients with elevated baseline FVIII had repeat FVIII levels. Persistent FVIII elevation was found in more than 75% of patients. At the 150% threshold, the prediction score ranged from 0 to 7 and included black race, female sex, prior stroke, hyperlipidemia, smoking, baseline FVIII > 200%, and baseline von Willebrand factor (vWF) level greater than 200%. At the 200% threshold, the prediction score ranged from 0-5 and included female sex, prior stroke, diabetes mellitus, baseline FVIII level greater 200%, and baseline vWF level greater than 200%. For each 1-point increase in score, the odds of persistent FVIII at both the 150% threshold (odds ratio [OR] = 10.4, 95% confidence interval [CI] 1.63-66.9, P = .0134) and 200% threshold (OR = 10.2, 95% CI 1.82-57.5, P = .0083) increased 10 times. CONCLUSION: Because an elevated FVIII level confers increased stroke risk, our model for anticipating a persistently elevated FVIII level may identify patients at high risk for recurrent stroke. FVIII may be a target for secondary stroke prevention.

Intravenous Tissue Plasminogen Activator for Wake-Up Stroke: A Propensity Score-Matched Analysis.

GOAL: To evaluate the safety and efficacy of intravenous (IV) tissue plasminogen activator (tPA) in the treatment of wake-up stroke (WUS) using propensity score (PS) analysis. MATERIALS AND METHODS: Consecutive acute ischemic stroke patients meeting inclusion criteria were retrospectively identified from our stroke registry between July 2008 and May 2014, and classified as stroke onset less than or equal to 4.5 hours treated with tPA (control; n = 369), tPA-treated WUS (n = 46), or nontreated WUS (n = 154). The primary outcome of interest for safety was symptomatic intracerebral hemorrhage (sICH), defined as parenchymal hemorrhage associated with a greater than or equal to 4-point increase in National Institutes of Health Stroke Scale (NIHSS) score. Multivariate logistic regression with adjustment for confounders and PS for receiving IV tPA assessed outcomes, along with PS-matched average treatment effect on the treated (ATT). FINDINGS: No significant difference was found in rates of sICH between tPA-treated WUS, nontreated WUS, and controls (2.2%, .7%, and 3%, respectively), or in the odds of sICH between tPA-treated WUS and controls (OR = .53, 95% CI = .06-4.60, P = .568). Among WUS patients, tPA treatment was significantly associated with higher odds of good functional outcome in fully adjusted analyses (OR = 7.22, 95% CI = 2.28-22.88, P = .001). The ATT of tPA for WUS patients demonstrated a significantly greater decrease in NIHSS score at discharge when compared to nontreated WUS patients (-4.32 versus -.34, P = .032). CONCLUSIONS: Comparable rates of sICH between treated WUS and stroke onset less than or equal to 4.5 hours treated with tPA suggest that tPA may be safely used to treat WUS. Superior outcomes for tPA-treated versus nontreated WUS subjects may suggest clinical efficacy of the treatment.

The impact of absent A1 segment on ischemic stroke characteristics and outcomes.

BACKGROUND: A1 segment is the proximal portion of anterior cerebral artery. Absence of the A1 segment can compromise anterior cerebral collateral blood flow. Few studies have examined the association of an absent A1 segment and ischemic stroke outcome. We sought to determine the association between A1 absence and affected vessel territory, stroke volume, and outcomes among patients with acute ischemic stroke (AIS). METHODS: A retrospective review of prospectively identified patients with AIS from July 2008 to March 2013 was performed. Patients without intracranial vascular imaging were excluded. We compared patients with absent A1 to patients with bilateral A1 segments in terms of demographics, stroke severity (as measured by National Institute of Health Stroke Scale [NIHSS]), vascular distribution, and in-hospital mortality using the chi-square test and logistic regression. RESULTS: Of the 1146 patients with AIS and intracranial vascular imaging, 5.9% patients (n = 68) had absent A1. Compared with other AIS patients, those with absent A1 were older (65 vs. 63 years old, respectively, P = .016). There was no difference between groups in terms of the vascular distribution or the side of the stroke. The median volume of the infracted tissue was similar across the groups even when it was stratified according to the Treatment of Acute Stroke Trial classification. Patients with an absent A1 had twice higher odds of in-hospital mortality (odds ratio, 2.4; 95% confidence interval, 1.1-5.2; P = .028); however, significance was lost after adjusting to age, NIHSS at baseline, and glucose on admission. Other outcome measures were similar across the groups. CONCLUSIONS: In our sample, patients with an absent A1 segment did not have a specific vascular distribution, larger infarct volume, or worse outcomes.

Cryptogenic stroke: clinical consideration of a heterogeneous ischemic subtype.

BACKGROUND: Cryptogenic stroke can be subdivided into 3 distinct categories: stroke of no determined cause (CyNC), stroke due to multiple etiologies (Cy >1), and stroke etiology unclear due to incomplete evaluation. Although these subdivisions may be very different from one another with respect to baseline features and outcomes, they are often reported as a composite group in clinical trials. METHODS: Patients treated at our academic institution between July 2008 and June 2013 for acute ischemic stroke were retrospectively assessed in our prospective registry. CyNC and Cy >1 patients were compared to other Trial of Org 10172 in Acute Stroke Treatment (TOAST) stroke subtypes and to each other using univariate analyses and multivariate logistic regression. The primary outcome of interest was good functional outcome, defined as a discharge modified Rankin Scale score of 0-2. RESULTS: Of the 1311 included patients, 260 (19.8%) experienced a CyNC and 49 (3.7%) experienced a Cy >1. Cy >1 classification was associated with history of atrial fibrillation (odds ratio [OR], 3.17; 95% confidence interval [CI], 1.16-6.12; P = .001). In comparison to other TOAST classifications, CyNC strokes were more likely to have good functional outcome (OR, 1.97; 95% CI, 1.38-2.82; P < .001) after adjusting for baseline National Institutes of Health Stroke Scale, admission glucose, age, and intravenous tissue plasminogen activator (IV tPA). CONCLUSIONS: Even after adjusting for higher IV tPA treatment rates, ischemic stroke patients with no identified cause had better outcomes than other TOAST groups. Conversely, patients coded as cryptogenic with more than 1 likely cause represent a different patient subpopulation. These data argue against the consolidation of cryptogenic stroke subcategories in future investigations.

A simple prediction score for developing a hospital-acquired infection after acute ischemic stroke.

BACKGROUND: Hospital-acquired infections (HAIs) are a major cause of morbidity and mortality in acute ischemic stroke patients. Although prior scoring systems have been developed to predict pneumonia in ischemic stroke patients, these scores were not designed to predict other infections. We sought to develop a simple scoring system for any HAI. METHODS: Patients admitted to our stroke center (July 2008-June 2012) were retrospectively assessed. Patients were excluded if they had an in-hospital stroke, unknown time from symptom onset, or delay from symptom onset to hospital arrival greater than 48 hours. Infections were diagnosed via clinical, laboratory, and imaging modalities using standard definitions. A scoring system was created to predict infections based on baseline patient characteristics. RESULTS: Of 568 patients, 84 (14.8%) developed an infection during their stays. Patients who developed infection were older (73 versus 64, P < .0001), more frequently diabetic (43.9% versus 29.1%, P = .0077), and had more severe strokes on admission (National Institutes of Health Stroke Scale [NIHSS] score 12 versus 5, P < .0001). Ranging from 0 to 7, the overall infection score consists of age 70 years or more (1 point), history of diabetes (1 point), and NIHSS score (0-4 conferred 0 points, 5-15 conferred 3 points, >15 conferred 5 points). Patients with an infection score of 4 or more were at 5 times greater odds of developing an infection (odds ratio, 5.67; 95% confidence interval, 3.28-9.81; P < .0001). CONCLUSION: In our sample, clinical, laboratory, and imaging information available at admission identified patients at risk for infections during their acute hospitalizations. If validated in other populations, this score could assist providers in predicting infections after ischemic stroke.

Von Willebrand factor drives the association between elevated factor VIII and poor outcomes in patients with ischemic stroke.

BACKGROUND AND PURPOSE: Despite clear roles of factor VIII (FVIII) and von Willebrand factor (vWF) in thrombosis, few studies have examined the relationship of these factors with acute ischemic stroke (AIS). We sought to determine whether concurrent elevation in FVIII and vWF was associated with adverse events and outcomes. METHODS: From our prospective stroke registry, patients consecutively admitted with AIS between July 2008 and October 2013 were included if both FVIII and vWF were measured during admission. The primary outcome was the modified Rankin Scale score on discharge. RESULTS: Among 1453 cases in our stroke registry, 148 patients with AIS met inclusion criteria; 62 patients (41.9%) had FVIII-/vWF-, 16 patients (10.8%) had FVIII+/vWF-, and 51 patients (34.5%) had FVIII+/vWF+. In the fully adjusted model, patients with FVIII+/vWF+ had increased odds of inpatient complications (odds ratio, 8.6; 95% confidence interval, 1.58-46.85; P=0.013) and neuroworsening (odds ratio, 3.2; 95% confidence interval, 1.18-8.73; P=0.022) than patients with FVIII-/vWF-. Adjusted for age, baseline stroke severity, and glucose, patients with FVIII+/vWF+ had increased odds of poor functional outcome (modified Rankin Scale>2; odds ratio, 2.87; 95% confidence interval, 1.16-7.06; P=0.021) than patients with FVIII-/vWF-. CONCLUSIONS: Concurrent FVIII/vWF elevation predicts higher odds of inpatient complications, neuroworsening, and worse functional outcomes for patients with AIS compared with patients with normal levels. Our findings suggest that FVIII and vWF levels may serve as clinically useful stroke biomarkers by providing risk profiles for patients with AIS.

Psychiatric disorders and function in adolescents with d-transposition of the great arteries.

OBJECTIVE: To compare adolescents with d-transposition of the great arteries (d-TGA) with healthy adolescents with respect to prevalence of psychiatric disorders and global psychosocial functioning. STUDY DESIGN: Subjects, consisting of 139 adolescents with d-TGA (16.1 ± 0.5 years) and 61 healthy adolescents (15.3 ± 1.1 years) without known risk factors for brain disorders, underwent a battery of assessments, including semistructured psychiatric interviews; self-report measures of depressive, anxiety, and disruptive behavior symptoms; and brain magnetic resonance imaging. Previous cognitive functioning and parental stress assessments at age 8 as well as parental post-traumatic stress at age 16 years were explored as potential risk factors predictive of overall psychiatric functioning. RESULTS: Compared with healthy adolescents, adolescents with d-TGA had higher lifetime prevalence of structured interview-derived attention-deficit/hyperactivity disorder (19% vs 7%, P = .03), along with reduced global psychosocial functioning (80.6 ± 11.2 vs 87.2 ± 7.1, P < .001) as well as significant increases in self-reported depressive (P = .01), anxiety (P = .02), and disruptive behavior symptoms (parent P < .001 and adolescent P = .03). Nevertheless, these youth scored in the nonclinical range on all self-report measures. Level of global psychosocial functioning was positively related to cognitive functioning (P < .001) and negatively related to parental stress (P = .008). CONCLUSIONS: Although adolescents with d-TGA demonstrate significant resilience to known neuropsychological and academic deficits, they show increased rates of attention-deficit/hyperactivity disorder and reduced psychosocial functioning. Impaired cognitive functioning and parental stress at younger age emerged as significant risk factors for psychiatric impairment.

Epigenomic Profiling of B Cell Subsets by CUT&Tag.

Epigenetic programs play a key role in regulating the development and function of immune cells. However, conventional methods for profiling epigenetic mechanisms, such as the post-translational modifications to histones, present several technical challenges that prevent a complete understanding of gene regulation. Here, we provide a detailed protocol of the Cleavage Under Targets and Tagmentation (CUT&Tag) chromatin profiling technique for identifying histone modifications in human and mouse lymphocytes.

Inpatient rehabilitation centers and concern for increasing volume of ischemic stroke patients requiring rehabilitation.

OBJECTIVES: To determine whether prolonged length of stay (pLOS) in ischemic stroke is related to delays in discharge disposition arrangement. METHODS: We designed a retrospective study to compare patients with acute ischemic stroke who experienced pLOS to those who did not experience pLOS. Patients who have had acute ischemic stroke between July 2008 and December 2010 were included unless they arrived >48 hours after time last seen normal, had an unknown last seen normal, or experienced an in-hospital stroke. pLOS was defined in our prospective stroke registry (before the generation of this research question) as hospitalization extended for ≥ 24 hours more than necessary to determine neurologic stability and next level of care/disposition for a given patient. We characterized the frequency of each cause of pLOS and further investigated the destinations that were more frequently associated with pLOS among patients with delay resulting from arranging discharge disposition. RESULTS: Of the 274 patients included, 106 (31.9%) had pLOS. Reasons for pLOS were discharge disposition (48.1%), non-neurologic medical complications (36.8%), delays in imaging studies (20.8%), awaiting procedure (10.4%), and neurologic complications (9.4%). Among patients with pLOS caused by delayed disposition, more than half were awaiting placement in an inpatient rehabilitation facility. CONCLUSIONS: For the majority of our patients, pLOS was caused by acquired medical complications and delayed disposition, most commonly inpatient rehabilitation. Further efforts are needed to prevent complications and further investigation is necessary to identify the factors that may contribute to delayed discharge to inpatient rehabilitation facilities, which may include delayed planning or heightened scrutiny of insurance companies regarding their beneficiaries.

A proposal for the classification of etiologies of neurologic deterioration after acute ischemic stroke.

BACKGROUND: Neurologic deterioration (ND) occurs in one third of patients with ischemic stroke and contributes to morbidity and mortality in these patients. Etiologies of ND and clinical outcome according to ND etiology are incompletely understood. METHODS: We conducted a retrospective investigation of all patients with ischemic stroke admitted to our center (July 2008 to December 2010), who were known to be last seen normal less than 48 hours before arrival. First-time episodes of ND during hospitalization were collected in which a patient experienced a 2-point increase or more in National Institutes of Health Stroke Scale score within a 24-hour period. Proposed etiologies of reversible ND include infectious, metabolic, hemodynamic, focal cerebral edema, fluctuation, sedation, and seizure, whereas new stroke, progressive stroke, intracerebral hemorrhage, and cardiopulmonary arrest were nonreversible. RESULTS: Of 366 included patients (median age 65 years, 41.4% women, 68.3% black), 128 (34.9%) experienced ND (median age 69 years, 42.2% women, 68.7% black). Probable etiologies of ND were identified in 90.6% of all first-time ND events. The most common etiology of ND, progressive stroke, was highly associated with poor outcome but not death. Etiologies most associated with mortality included edema (47.8%), new stroke (50%), and intracerebral hemorrhage (42.1%). CONCLUSIONS: In the present study, the authors identified probable etiologies of ND after ischemic stroke. Delineating the cause of ND could play an important role in the management of the patient and help set expectations for prognosis after ND has occurred. Prospective studies are needed to validate these proposed definitions of ND.

Infections present on admission compared with hospital-acquired infections in acute ischemic stroke patients.

BACKGROUND: To date, few studies have assessed the influence of infections present on admission (POA) compared with hospital-acquired infections (HAIs) on neurologic deterioration (ND) and other outcome measures in acute ischemic stroke (AIS). METHODS: Patients admitted with AIS to our stroke center (July 2010 to December 2010) were retrospectively assessed. The following infections were assessed: urinary tract infection, pneumonia, and bacteremia. Additional chart review was performed to determine whether the infection was POA or HAI. We assessed the relationship between infections in ischemic stroke patients and several outcome measures including ND and poor functional outcome. A mediation analysis was performed to assess the indirect effects of HAI, ND, and poor functional outcome. RESULTS: Of the 334 patients included in this study, 77 had any type of infection (23 POA). After adjusting for age, National Institutes of Health Stroke Scale at baseline, glucose on admission, and intravenous tissue plasminogen activator, HAI remained a significant predictor of ND (odds ratio [OR]=8.8, 95% confidence interval [CI]: 4.2-18.7, P<.0001) and poor functional outcome (OR=41.7, 95% CI: 5.2-337.9, P=.005), whereas infections POA were no longer associated with ND or poor functional outcome. In an adjusted analysis, we found that 57% of the effect from HAI infections on poor functional outcome is because of mediation through ND (P<.0001). CONCLUSIONS: Our data suggests that HAI in AIS patients increases the odds of experiencing ND and subsequently increases the odds of being discharged with significant disability. This mediated effect suggests a preventable cause of ND that can thereby decrease the odds of poor functional outcomes after an AIS.

IL-6/STAT3 Signaling Axis Enhances and Prolongs Pdcd1 Expression in Murine CD8 T Cells.

CD8 cytotoxic T cells are a potent line of defense against invading pathogens. To aid in curtailing aberrant immune responses, the activation status of CD8 T cells is highly regulated. One mechanism in which CD8 T cell responses are dampened is via signaling through the immune-inhibitory receptor Programmed Cell Death Protein-1, encoded by Pdcd1. Pdcd1 expression is regulated through engagement of the TCR, as well as by signaling from extracellular cytokines. Understanding such pathways has influenced the development of numerous clinical treatments. In this study, we showed that signals from the cytokine IL-6 enhanced Pdcd1 expression when paired with TCR stimulation in murine CD8 T cells. Mechanistically, signals from IL-6 were propagated through activation of the transcription factor STAT3, resulting in IL-6-dependent binding of STAT3 to Pdcd1 cis-regulatory elements. Intriguingly, IL-6 stimulation overcame B Lymphocyte Maturation Protein 1-mediated epigenetic repression of Pdcd1, which resulted in a transcriptionally permissive landscape marked by heightened histone acetylation. Furthermore, in vivo-activated CD8 T cells derived from lymphocytic choriomeningitis virus infection required STAT3 for optimal Programmed Cell Death Protein-1 surface expression. Importantly, STAT3 was the only member of the STAT family present at Pdcd1 regulatory elements in lymphocytic choriomeningitis virus Ag-specific CD8 T cells. Collectively, these data define mechanisms by which the IL-6/STAT3 signaling axis can enhance and prolong Pdcd1 expression in murine CD8 T cells.