For the purposes of analyses, headache

frequency was categorized as days per month within the following categories: <1 per month, 1-4 month, 5-9 per month, and ≥10 per month. Analyses were conducted using SAS Version 9 (Copyright © 2002-2008 SAS Institute Inc., Cary, NC, USA). Nonresponse bias was examined contrasting differential response rates across demographic strata on: sex, age, race, region of the country, population density of geographic location, annual household income, and household size (ie, number EPZ-6438 nmr of members in the household) using descriptive statistics. Data were reported for those with and without “severe” headache. Sex-specific prevalence for those with “severe” headache was divided by headache type, and sex-specific prevalence rates within each headache type were calculated by age, race, and annual household income. Log-binomial models were used to calculate adjusted sex-stratified PRs by headache type for sociodemographic variables. These models estimated PRs and 95% confidence intervals (CIs)

for each individual sociodemographic variable adjusted for all other sociodemographic variables. Adjusted PRs were obtained from adjusted log-binomial models, which were also used to determine female to male adjusted PRs for each headache type stratified on the 5 sociodemographic AZD2014 research buy categories (adjusting for all other sociodemographic variables). Within each headache type, unadjusted sex-specific prevalence and PRs were calculated for the effects of headache symptoms, headache frequency (days per month), average headache pain intensity, headache-related disability and impairment, headache diagnoses assigned by an HCP, emergency department/urgent care clinic use, and medication use (acute and preventive for headache MCE公司 and other conditions). Log-binomial models were used to estimate sex PRs and 95% CIs. Data on headache impact, headache-related disability, healthcare resource utilization, and medication use were reported as the percentage of the sample who responded (participants

with missing data were not included in the denominator for the items for which they did not respond). One hundred twenty thousand households, containing a total of 257,339 household members, were contacted to participate in the AMPP Study survey. Surveys were returned by 77,879 households (64.9% response rate) yielding data for 162,756 individual household members aged ≥12 years old (Table 1). Respondents were primarily female (52.6%, N = 85,571) and Caucasian (86.6%, N = 140,948). Response rates did not differ substantially between males (62%) and females (64%), but were higher in Caucasians (65%) than in African Americans (56%, P < .01) and in those aged ≥50 years old (P < .01). Response rates did not differ significantly by geographic region, population density, or annual household income.

7-fold higher in patients with diastolic hypertension.17,18 In addition, Donati et al. reported that even in non-obese, non-diabetic high blood pressure patients, the prevalence of fatty liver was three times higher than in healthy individuals. Further such patients showed high levels of HOMA-IR, indicating insulin resistance.19 The pathogenesis of hypertension is influenced by various CP-673451 supplier factors, such as salt intake, and also

is associated with insulin resistance. It is important to know that even non-obese high blood pressure patients with no other lifestyle-related diseases are likely to develop NAFLD if they have insulin resistance. In Japan, large-scale studies on hypertension and NAFLD are currently underway, including among subjects with chronic kidney disease (CKD). Recently, we reported the prevalence of CKD in 174 NAFLD patients. The prevalence of CKD was significantly higher in NASH patients (19 of 92; 21%) than SS patients (5 of 82; 6%), and associated with a higher body mass index and the presence of hypertension.20 Dyslipidemia is a generic term describing a clinical condition in which the levels of cholesterol esters or triglycerides increase in the Gefitinib chemical structure blood: high levels of triglycerides (150 mg/dL or higher) and LDL cholesterol (140 mg/dL or higher), with decreased levels of HDL cholesterol (less than 40 mg/dL) are each risk factors MCE for other diseases. In the

National Health and Nutrition Examination Survey conducted in 2007, the percentage of subjects suspected of dyslipidemia (including 9.7%

currently under treatment) was 44.1%, and that of normal subjects was 55.9%. Dyslipidemia in NAFLD often involves hypertriglyceridemia and decreased blood levels of HDL cholesterol. This is due to the insufficient effects of lipoprotein lipase (LPL), which leads to a decreased metabolism of triglyceride-rich lipoproteins into HDL cholesterol. In addition, there is also an increased synthesis of very-low density lipoprotein (VLDL). The incidence of pediatric NAFLD in Japan is increasing in proportion to the increase in the prevalence of childhood obesity. In a previous study conducted on children aged 6–15 years, Tominaga et al. reported that the prevalence of NAFLD was 3.4% in children aged 6–10 years and 5.2% in those aged 11–15 years.21 In addition, the prevalence of NAFLD in children who met the diagnostic criteria for pediatric metabolic syndrome was 40.0% in those diagnosed with pre-metabolic syndrome, and 76.8% in those who fulfilled the criteria for metabolic syndrome. Tsuruta et al. also reported that, in a similar study conducted in 2007 on 288 junior high school students (13–15 years old), 5.9% were obese, the prevalence of NAFLD was 4.5%, and obesity and ALT levels of 30 IU/L or higher were independent risk factors for NAFLD in children.

In this issue of HEPATOLOGY, Marques et al.23 report on a study demonstrating that DAMP molecules released from necrotic hepatocytes recruit and activate neutrophils in the liver, which, in turn, amplify AILI. Three experimental approaches were employed to elucidate the pathological role of neutrophils in AILI. Consistent with published reports,24, 25 the present study shows that neutrophil depletion by an anti-Gr-1 antibody significantly attenuates AILI. Furthermore, the combined use of a CXC chemokine receptor 2 antagonist and a formyl peptide receptor 1 (FPR1) antagonist also blocks hepatic recruitment of neutrophils and mitigates AILI. This approach is based on the

investigators’ previous finding that an intravascular gradient of chemokines and mitochondria-derived formyl peptides collaboratively guide neutrophils Z-VAD-FMK supplier to sites of ABT-263 liver necrosis.26 These two separate in vivo studies demonstrate that liver injury initiated by APAP challenge is amplified by infiltrating neutrophils. The investigators

further examined the cytotoxic potential of neutrophils against hepatocytes. Neutrophils isolated from healthy individuals were cocultured with APAP-treated HepG2 cells. Data show that the cytotoxicity of HepG2 cells is enhanced by neutrophils in a cell-contact–dependent manner, and that necrotic HepG2 cells significantly increase reactive oxygen species production by netrophils. Collectively, these findings provide evidence to support a pathological role of neutrophils during AILI. Traumatic injury is known to cause “septic-like” systemic MCE公司 inflammatory response in the absence of infection.27 The underlying mechanism is recently elucidated by the detection of mitrochondrial DNA (mtDNA) and formyl peptides released in the serum of trauma patients.28 Circulating mitochondrial DAMPs activate neutrophils through Toll-like receptor 9 (TLR-9) and FPR1, respectively, thereby eliciting neutrophil-mediated organ injury.28 Because APAP causes mitochrondria damage, it is likely that mitochondrial

contents are released into the circulation. Evidence supporting this hypothesis is provided by a recent study detecting circulating mitochondrial biomarkers, including mtDNA and glutamate dehydrogenase, in the serum of patients with AILI.29 Similarly, the present study shows a significant increase in serum mtDNA levels in acute liver failure patients, compared to healthy volunteers. The elevation of circulating mtDNA is also observed in APAP-treated mice. The effect of mtDNA release on AILI is revealed by a significant decrease of liver injury in TLR-9−/− mice, compared to wild-type mice. This finding is consistent with a published report of protection against AILI by TLR-9 antagonists and in TLR-9−/− mice.30 APAP-induced liver failure is accompanied by other tissue complications, such as encephalopathy, coagulopathy, renal failure, metabolic derangements, cardiovascular compromises, and severe lung injury.

Although a unified criteria for combined HCC-CC is still not available, it is generally accepted that a firm diagnosis of combined HCC-CC requires evidence of HCC differentiation (Fig. 2a), such as trabecular growth

pattern, bile production, or bile canaliculi as well as clear evidence of CC (Fig. 2b), such as true glandular structures formed by biliary-type epithelium, mucin production or prominent desmoplastic stoma.4,14 In addition, ideally, an interface of these two components showing they intermingle intimately with each other should also be appreciated (Fig. 3). Practically, a definitive diagnosis always requires the use of immunohistochemical and special stains to demonstrate LDE225 both hepatocytic and biliary phenotypes. Commonly used stains include Hep Par 1 (Fig. 4a), polyclonal NVP-BKM120 concentration carcinoembryonic antigen (Fig. 4b), or CD10 for the hepatocytic differentiation, and mucin (Fig. 4c), CK7, and CK19 (Fig. 4d) stains for the biliary differentiation. Combined HCC-CC often expresses both biliary cytokeratins and markers of HCC, and is an important diagnosis to consider when there is an apparently conflicting or overlapping immunophenotype.15 While fibrolamellar carcinoma, a variant of HCC, very rarely occurs in association with CC, a single case of combined fibrolamellar HCC-CC has been reported previously.16 Studies with a series of combined fibrolamellar HCC-CC

are needed to further characterize this rare neoplasm. Glypican-3 (GPC3) is a novel serological and immunohistochemical marker of hepatocellular carcinoma.17–19 A recent study to examine GPC3 immunoreactivity MCE in combined HCC-CC shows the expression is sensitive and specific to the HCC component of combined HCC-CC but few cases also show weak immunoreactivity in the cholangiocarcinoma component of combined HCC-CC.20 While the positivity of GPC3 in the cholangiocarcinoma component may be a drawback, this antibody may offer as an additional immunohistochemical stain in diagnosing combined HCC-CC, if used along with

other antibodies and in careful correlation with morphology. The cell of origin of combined HCC-CC has been a matter of dispute. Overall three possibilities may be postulated regarding its cell of origin: (i) collision (double) tumor of HCC and CC that incidentally coexist in the same liver; (ii) subsequent differentiation of HCC or CC into the other component; and (iii) the cancer derives from the hepatic progenitor cells (Fig. 5). The fact that the HCC and CC elements intermingle with each other in a transitional area in most combined HCC-CC makes the first hypothesis less likely. Depending on various investigations, patients with combined HCC-CC share similar clinical and pathological features with patients with HCC4,21 or CC12,15,22 or the tumors are clinicopathologically different from those of CC11 or HCC.

38 Furthermore, the association of HBsAg reductions with sustained responses was observed across the major genotypes (A-D).40 Although these low on-treatment levels were reached by less than 25% of the treated patients, these encouraging data suggest a potential role for HBsAg levels in predicting the response to PEG-IFN. This

could encourage or motivate patients to complete their course of therapy. The ability to determine who is most unlikely to achieve a sustained response to PEG-IFN might be of more practical value for patient management. The early identification of nonresponders would allow the discontinuation of therapy and/or changes in the treatment strategy for these patients. High negative predictive values (NPVs) for response have been reported for Copanlisib in vitro both HBeAg-positive and HBeAg-negative patients. Sonneveld et al.26 reported an NPV of 97% for 202 PEG-IFNα2b–treated, HBeAg-positive patients (74% with genotype A or D HBV), which was based on any decline in HBsAg levels at week 12. An HBsAg decline at week 12 had an NPV of 82% in another large study of PEG-IFNα2a therapy (88% with genotype B or C HBV).41 The Hong Kong study reported an NPV of 86% for HBsAg levels < 1500 IU/mL at month 3 and an NPV of 89% for levels <

300 IU/mL at month 6.35 The Chinese study also showed that an Caspase cleavage HBsAg level < 1500 IU/mL at week 12 had an NPV of 91%, whereas the NPV was 95% when the cutoff level was 2890 IU/mL at week 24.36 For HBeAg-negative patients, Moucari et al.38 reported medchemexpress an NPV of 90% for an HBsAg decline of 0.5 log10 IU/mL at week 12 and an NPV of 97% for a decline of 1 log10 IU/mL at week 24 in a mixed-genotype population. In a population that mainly

had genotype D, Rijckborst et al.39 reported an NPV of 100%, which was based on a combination of an HBsAg decline and a 2 log10 IU/mL decline in HBV DNA levels from the baseline to week 12. This proposed stopping rule was recently validated in another cohort of patients treated with PEG-IFN.42 These apparently robust early stopping rules with high NPVs could help with the management of patients and may even encourage patients to consider PEG-IFN as first-line therapy. This may be particularly applicable when the alternative is most likely lifelong therapy with NAs, especially for patients with HBeAg-negative disease. On the basis of these studies in different populations with different genotypes, week 12 of IFN-based therapy seems to be the right time for assessing an HBsAg decline (Table 4). However, the most appropriate degree of this decline still needs to be established before it can be adopted by the community as a guide for clinical practice. HBsAg profiles were also analyzed retrospectively in hepatitis C virus (HCV)/HBV-coinfected individuals treated with PEG-IFN and ribavirin for their predominant HCV infection.

Our 2 patients were middle-aged women, with severe chronic anemia (average hemoglobin: 1.45 g/dL), and received multiple blood transfusions (average: 3250 mL) over a period of 5-7 days. They developed thunderclap headache and other symptoms about 1 week after the last blood transfusion. Cerebral vasoconstrictions INCB024360 manufacturer were demonstrated by magnetic resonance angiography and transcranial color-coded sonography. PRES was found

in both of them using magnetic resonance imaging, and one of them also had cytotoxic edema on diffusion weighted image. RCVS with PRES is one complication of blood transfusion in patients under chronic severe anemia (especially when hemoglobin level increased for more than 5 g/dL), particularly in Asian women with menorrhagia. Blood pressure surge and the occurrence of severe headaches or other neurological symptoms should be aggressively monitored within 10 days after the last blood transfusion. “
“Limited and conflicting data exist regarding the prevalence of psychiatric disorders, particularly substance use disorders (SUDs), among migraineurs in inpatient Z-VAD-FMK clinical trial clinical settings. As part of a larger

cross-sectional study, 181 substance-dependent inpatients completed a structured psychiatric interview and measures of psychiatric symptoms and migraine. Standardized mean differences were used to quantify differences between inpatients with and without migraine across 4 domains of predictors (demographic variables, non-SUD psychiatric diagnoses, specific SUDs, and self-reported psychiatric symptoms). The predictors within each domain that best discriminated between the migraine and no-migraine groups were identified using a classification tree approach with Bonferroni corrections. These candidate predictors were subsequently entered into a multivariate logistic regression to predict migraine status, which was then replicated using bootstrapping of 500 samples. Associations between migraine status and SUD treatment dropout were also examined.

medchemexpress Forty-four of the 181 (24.3%) participants met criteria for migraine. Migraineurs were more likely to be female (34.8% vs 18.3%) and reported higher levels of current anxiety symptoms (mean [standard deviation]: 19.7 [11.0] vs 11.3 [10.3]). Having a lifetime diagnosis of generalized anxiety disorder (56.8% vs 27%, odds ratio 3.47, 95% confidence interval [CI] 1.39-10.58) or a current diagnosis of alcohol dependence (45.5% vs 24.1%, odds ratio 3.79, 95% CI 1.63-13.62) was associated with more than a 3-fold risk of migraine. These 4 variables in combination were forced into the final multivariate model, which differentiated well between those with and without migraine (area under the receiver operating characteristic curve = 0.81; 95% CI 0.73-0.88). Migraine was not differentially associated with increased risk for SUD treatment dropout (13.6% vs 16.

The use of FFP can be complicated by an increasing risk of transfusion-transmitted diseases, allergic reactions and even anaphylactic shock, especially in those with immunoglobulin A (IgA) deficiency when IgA-depleted FFP is not used. FXI concentrate (plasma derived, heat treated) is another option offered in some countries, in the absence of recombinant FXI. It is efficient in predicting the expected incremental increase

in FXI levels when a given dosage is administered, and since it has a long half-life, this treatment can be given on alternate days. The target level should be 30–40 IU dL−1. The caveat of the use of FXI concentrates is that both currently available products [Bio Products Laboratory selleck (BPL), selleck screening library UK and LFB Biomedicaments, France] have been associated with thrombosis even after adding heparin to the antithrombin in the BPL product, and antithrombin and heparin to the C1 esterase in the LFB product [17, 24, 25]. Furthermore, patients with undetectable plasma levels of FXI are at risk of developing inhibitors following exposure to the concentrates [26], and they cannot be used in IgA deficient patients. Thus, before these concentrates can be prescribed for use, screening for antibodies is mandatory in patients with undetectable FXI levels who were previously exposed to FFP, FXI concentrates, or immunoglobulin. Low-dose (15–30 μg kg−1)

recombinant factor VIIa (rFVIIa), a bypassing agent, has been successfully used in patients with severe FXI deficiency, both with and without inhibitors [27, 28]. Caution is required when used at higher doses, such as those regularly used to treat haemophilia A and B, because of the increased risk of thrombosis [29, 上海皓元 30]. It is the only treatment available for patients with inhibitors, and has recently been suggested for primary treatment to avoid exposure to blood

products. Antifibrinolytic agents, e.g. tranexamic acid or 6-aminocaproic acid, are currently used as monotherapy for minor procedures such as before tooth extraction, or in combination with very low-dose rFVIIa or FFP in major procedures. Altogether, before planning prophylactic treatment for patients with severe FXI deficiency, the following issues must be addressed: Site and type of surgery [31] Presence of an inhibitor Combined haemostatic defects Thrombotic risk Volume overload Presence of IgA deficiency Previous exposure/lack of exposure to blood products Environmental interactions . In conclusion, therapy tailored to an individual’s risk and type of procedure constitutes the ideal management of FXI deficient patients. It remains to be established whether one of the global coagulation tests, including assays of fibrinolysis and/or clot structure, will eventually efficiently predict the bleeding risk of a given individual before innovative prophylactic treatment can be recommended.

Bucillamine is a low molecular weight thiol antioxidant that is capable of rapidly entering cells. We hypothesized that bucillamine acts by replenishing glutathione levels, thus reducing neutrophil activation, modulating Bax/Bcl-2 expression, and subsequently, attenuating the effects of warm ischemia–reperfusion injury (IRI) in the liver. Methods:  The effect of bucillamine was studied in a rat model of liver IRI with 45 min of partial (70%) liver ischemia and 3 h of reperfusion. Liver injury was Carfilzomib nmr assessed by measuring serum

transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and liver histology. Oxidative stress was quantified by measuring F2 isoprostane and glutathione levels. Leukocyte adhesion was assessed by intravital microscopy, and inflammatory cytokine response was assessed by measuring serum cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels. Bax and Bcl-2 expression was measured by reverse transcription–polymerase chain reaction. Results:  The model produced significant liver injury with elevated transaminases and an acute inflammatory response. Bucillamine reduced the liver injury, as indicated by reduced AST (932 ± 200.8 vs 2072.5 ± 511.79, P < 0.05). Bucillamine reduced Bax expression, serum CINC-1 levels, and neutrophil adhesion, and upregulated Bcl-2. However,

bucillamine did not selleck affect tissue glutathione levels nor the levels of oxidative stress, as measured by plasma and hepatic F2 isoprostane levels. Conclusions:  Bucillamine reduces warm ischemia–reperfusion in the liver by inhibiting neutrophil activation and modulating Bax/Bcl-2 expression. “
“Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu City, Taiwan Universty of Utrecht, Utrecht, the

Netherlands Christian Medical College, Vellore, India VU University Medical Center, Amsterdam, medchemexpress the Netherlands Sorafenib—a broad kinase inhibitor—is a standard therapy for advanced hepatocellular carcinoma (HCC) and has been shown to exert antifibrotic effects in liver cirrhosis, a precursor of HCC. However, the effects of sorafenib on tumor desmoplasia—and its consequences on treatment resistance—remain unknown. We demonstrate that sorafenib has differential effects on tumor fibrosis versus liver fibrosis in orthotopic models of HCC in mice. Sorafenib intensifies tumor hypoxia, which increases stromal-derived factor 1 alpha (SDF-1α) expression in cancer and stromal cells and, subsequently, myeloid differentiation antigen–positive (Gr-1+) myeloid cell infiltration. The SDF-1α/C-X-C receptor type 4 (CXCR4) pathway directly promotes hepatic stellate cell (HSC) differentiation and activation through the mitogen-activated protein kinase pathway.

Serum iron levels are determined both by intestinal absorption and macrophage recycling of iron from hemoglobin because there is no efficient MAPK Inhibitor Library pathway for iron excretion.[10] Regulatory effectors that modulate intestinal iron absorption probably also modulate the release of iron from tissue macrophages and hepatocytes. Hepcidin appears to be such a regulatory effector. It is a small, cysteine-rich peptide, cleaved from a larger precursor.[11-13] Hepcidin, which was originally isolated from human serum and urine as a peptide with antimicrobial activity,[11,

13] is a hormone exclusively synthesized in the liver and a soluble regulator that acts to attenuate both intestinal iron absorption and iron release from reticuloendothelial macrophages.[12, 14] Increased plasma iron from macrophage recycling of aged red blood cells or from intestinal absorption of iron stimulates hepatocytes through several signaling pathways to produce more hepcidin. Ferroportin is an iron exporter on the surface of absorptive intestinal enterocytes, macrophages, hepatocytes, and placental cells, all of which release iron into plasma.[15-17] Circulating hepcidin can Doxorubicin in vitro bind to ferroportin, cause internalization, and trap iron

in hepatocytes, macrophages, and absorptive enterocytes.[18] Thus, coupling the internalization of ferroportin to hepcidin levels generates a homeostatic loop regulating the iron plasma level and the tissue distribution of iron. 上海皓元 Knowledge of how hepcidin transcription is regulated within hepatocytes appears to be indispensable for understanding the mechanisms underlying hepatic iron overload in chronic hepatitis

C because hepcidin is the central regulator of systemic iron homeostasis. Important elements of the signaling pathway present on the hepatic plasma membrane that affect hepcidin transcription include transferrin receptor 2 (TfR2),[19] HFE,[20] which is the protein affected in the most common form of genetic hemochromatosis, and hemojuverin (HJV),[21] a member of the bone morphogenetic protein (BMP) receptor family. The mechanisms by which TfR2, HFE, and HJV are linked to changes in hepcidin transcription are incompletely understood, but the discovery of HJV revealed that the well-known sons of mothers against decapentaplegic (SMAD) signal transduction pathway was important in this process.[22] Notably, animals that lack hepatocyte SMAD4, a protein that combines with other members of the SMAD family to regulate transcription of target genes, develop significant iron overload associated with a profound reduction in hepcidin expression.[23] Interleukin 6 (IL-6) activates hepcidin transcription through a pathway that involves janus kinase-signal transducer and activator of transcription (STAT) signaling and a binding site for the transcription factor STAT3.

In diagnosing congenital bleeding disorders, parental ethnic background and whether there is consanguinity in the marriage are very important. Some bleeding disorders are more common within certain ethnic groups (for example, incidence of factor XI deficiency is increased in Ashkenazy Jews) [3]. Consanguineous marriages will increase risk for birth of neonates with an autosomal recessive bleeding disorder. The presence of family history for a

bleeding disorder will also provide insight into the heritable Selleckchem R788 basis for the haemorrhagic state. However, absence of family history for a bleeding disorder cannot exclude occurrence of severe bleeding disorders. For example, approximately a third of severe haemophilia A patients do not have a positive family history. An otherwise normal neonate with thrombocytopenia is suggestive of NAIT or transfer of maternal antibodies. On the other hand, coagulopathies are usually secondary events. Congenital infection, sepsis, significant metabolic disorders

(such as tyrosinaemia) and Kasabach-Merritt syndrome [4] are a few of the many conditions that need to be considered. Other skeletal this website abnormalities such as absence of thumb or radii are obvious tips for conditions such as thrombocytopenia with absent radii or Fanconi anaemia [5]. Although giving vitamin K to neonates is almost a universal routine, it is still important to ascertain that the vitamin K was indeed administered to patients where vitamin K deficiency is suspected. Determination of platelet counts is relatively simple. However, it is more challenging to accurately test for platelet function and interpret the results since artefacts can be introduced because of a difficult venipuncture. As for assessing the fluid phase compartment of the haemostatic system, it is critical

to use age appropriate reference ranges to determine whether coagulation proteins are truly normal. There are significant challenges implementing such recommendations because of the following reasons: (i) most laboratories will not be able to establish their own reference ranges because it is very resource intensive, (ii) reference ranges that have been established by a few groups around the world are reagent and analyser MCE公司 specific. Therefore, what has been established in one laboratory may not be portable to other institutions, (iii) difficult venipunctures can hamper sample integrity. The prolonged Prothrombin time (PT) in neonates reflects decreased plasma concentrations of vitamin K-dependant factors, whereas the prolonged Partial tromboplastin time (PTT) stems from decreased plasma levels of contact factors as well [6–11]. The levels of FVIII, FV and FXIII, correlate well with adult boundaries. Plasma concentrations of fibrinogen may be skewed upwards despite that thrombin clotting time may be prolonged as a result of a normally present ‘foetal’ fibrinogen [12]. Bleeding time, the test that measures primary haemostasis, e.