Efficacy and safety of outpatient fludarabine, cyclophosphamide, and rituximab based allogeneic hematopoietic cell transplantation in adults with severe aplastic anemia.

The age effect in severe aplastic anemia (SAA) following allogeneic hematopoietic cell transplantation (HCT) favors the use of reduced intensity conditioning (RIC) regimens in older adults. We implemented a non-myeloablative regimen consisting of fludarabine, cyclophosphamide, and rituximab (FCR) to improve HCT outcomes in SAA. Patients who underwent first HCT for SAA utilizing an FCR regimen between January 2016 and May 2022 were included. Outcomes analyzed included time to engraftment, incidence of graft failure, GVHD, viral reactivation, disease recurrence, and GVHD-free, relapse-free survival (GRFS). Among 24 patients included, median age was 43.5 years (22-62) and a variety of donor types and stem cell sources were represented. At median follow-up of 26.9 months (2.4-72.7), no cases of grade III-IV acute (aGVHD) or severe chronic GVHD (cGVHD) were recorded. Viral reactivation was minimal, and there were no cases of graft failure or PTLD, with 100% disease-free and overall survival at last follow up. The estimate of 1-year GRFS was 86.3% (95% CI: 72.8-100%), with moderate cGVHD accounting for all events. The FCR regimen in SAA was well tolerated, even in older adults, with 100% disease-free survival with low GVHD and infection rates. These encouraging findings should be validated in larger prospective trials.

Monoallelically expressed noncoding RNAs form nucleolar territories on NOR-containing chromosomes and regulate rRNA expression.

Out of the several hundred copies of rRNA genes arranged in the nucleolar organizing regions (NOR) of the five human acrocentric chromosomes, ~50% remain transcriptionally inactive. NOR-associated sequences and epigenetic modifications contribute to the differential expression of rRNAs. However, the mechanism(s) controlling the dosage of active versus inactive rRNA genes within each NOR in mammals is yet to be determined. We have discovered a family of ncRNAs, SNULs (Single NUcleolus Localized RNA), which form constrained sub-nucleolar territories on individual NORs and influence rRNA expression. Individual members of the SNULs monoallelically associate with specific NOR-containing chromosomes. SNULs share sequence similarity to pre-rRNA and localize in the sub-nucleolar compartment with pre-rRNA. Finally, SNULs control rRNA expression by influencing pre-rRNA sorting to the DFC compartment and pre-rRNA processing. Our study discovered a novel class of ncRNAs influencing rRNA expression by forming constrained nucleolar territories on individual NORs.

Identifying key underlying regulatory networks and predicting targets of orphan C/D box SNORD116 snoRNAs in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder characterized principally by initial symptoms of neonatal hypotonia and failure-to-thrive in infancy, followed by hyperphagia and obesity. It is well established that PWS is caused by loss of paternal expression of the imprinted region on chromosome 15q11-q13. While most PWS cases exhibit megabase-scale deletions of the paternal chromosome 15q11-q13 allele, several PWS patients have been identified harboring a much smaller deletion encompassing primarily SNORD116. This finding suggests SNORD116 is a direct driver of PWS phenotypes. The SNORD116 gene cluster is composed of 30 copies of individual SNORD116 C/D box small nucleolar RNAs (snoRNAs). Many C/D box snoRNAs have been shown to guide chemical modifications of other RNA molecules, often ribosomal RNA (rRNA). However, SNORD116 snoRNAs are termed 'orphans' because no verified targets have been identified and their sequences show no significant complementarity to rRNA. It is crucial to identify the targets and functions of SNORD116 snoRNAs because all reported PWS cases lack their expression. To address this, we engineered two different deletions modelling PWS in two distinct human embryonic stem cell (hESC) lines to control for effects of genetic background. Utilizing an inducible expression system enabled quick, reproducible differentiation of these lines into neurons. Systematic comparisons of neuronal gene expression across deletion types and genetic backgrounds revealed a novel list of 42 consistently dysregulated genes. Employing the recently described computational tool snoGloBe, we discovered these dysregulated genes are significantly enriched for predicted SNORD116 targeting versus multiple control analyses. Importantly, our results showed it is critical to use multiple isogenic cell line pairs, as this eliminated many spuriously differentially expressed genes. Our results indicate a novel gene regulatory network controlled by SNORD116 is likely perturbed in PWS patients.

Generation of isogenic models of Angelman syndrome and Prader-Willi syndrome in CRISPR/Cas9-engineered human embryonic stem cells.

Angelman Syndrome (AS) and Prader-Willi Syndrome (PWS), two distinct neurodevelopmental disorders, result from loss of expression from imprinted genes in the chromosome 15q11-13 locus most commonly caused by a megabase-scale deletion on either the maternal or paternal allele, respectively. Each occurs at an approximate incidence of 1/15,000 to 1/30,000 live births and has a range of debilitating phenotypes. Patient-derived induced pluripotent stem cells (iPSCs) have been valuable tools to understand human-relevant gene regulation at this locus and have contributed to the development of therapeutic approaches for AS. Nonetheless, gaps remain in our understanding of how these deletions contribute to dysregulation and phenotypes of AS and PWS. Variability across cell lines due to donor differences, reprogramming methods, and genetic background make it challenging to fill these gaps in knowledge without substantially increasing the number of cell lines used in the analyses. Isogenic cell lines that differ only by the genetic mutation causing the disease can ease this burden without requiring such a large number of cell lines. Here, we describe the development of isogenic human embryonic stem cell (hESC) lines modeling the most common genetic subtypes of AS and PWS. These lines allow for a facile interrogation of allele-specific gene regulation at the chromosome 15q11-q13 locus. Additionally, these lines are an important resource to identify and test targeted therapeutic approaches for patients with AS and PWS.

A calibrated cell-based functional assay to aid classification of MLH1 DNA mismatch repair gene variants.

Functional assays provide important evidence for classifying the disease significance of germline variants in DNA mismatch repair genes. Numerous laboratories, including our own, have developed functional assays to study mismatch repair gene variants. However, previous assays are limited due to the model system employed, the manner of gene expression, or the environment in which function is assessed. Here, we developed a human cell-based approach for testing the function of variants of uncertain significance (VUS) in the MLH1 gene. Using clustered regularly interspaced short palindromic repeats gene editing, we knocked in MLH1 VUS into the endogenous MLH1 loci in human embryonic stem cells. We examined their impact on RNA and protein, including their ability to prevent microsatellite instability and instigate a DNA damage response. A statistical clustering analysis determined the range of functions associated with known pathogenic or benign variants, and linear regression was performed using existing odds in favor of pathogenicity scores for these control variants to calibrate our functional assay results. By converting the functional outputs into a single odds in favor of pathogenicity score, variant classification expert panels can use these results to readily reassess these VUS. Ultimately, this information will guide proper diagnosis and disease management for suspected Lynch syndrome patients.

A Practical Review for Implementing Peer Assessments Within Teams.

Objective. The objective of this review is to maximize the benefit of peer assessments in teamwork settings in professional pharmacy curricula.Findings. Best practices do not exist for using peer assessments in academic settings. The studies on peer assessments that we reviewed applied various conditions: Some studies used peer assessments of teams for formative assessments, while others used them for summative assessments; some assessed teamwork at a limited number of time points, while some assessed multiple time points; some attached student names to the assessments, while some were anonymous; and some explained why the tool was being used, while others offered no explanation.Conclusion. To use peer assessments most beneficially, instructors must define the purpose for their use, explain the purpose of teamwork, orient students to the tool being used, assess teamwork over time, provide feedback, minimize grades associated with the assessment, and use partial anonymity when collecting feedback.

Inverse Temperature Dependence of Charge Carrier Hopping in Quantum Dot Solids.

In semiconductors, increasing mobility with decreasing temperature is a signature of charge carrier transport through delocalized bands. Here, we show that this behavior can also occur in nanocrystal solids due to temperature-dependent structural transformations. Using a combination of broadband infrared transient absorption spectroscopy and numerical modeling, we investigate the temperature-dependent charge transport properties of well-ordered PbS quantum dot (QD) solids. Contrary to expectations, we observe that the QD-to-QD charge tunneling rate increases with decreasing temperature, while simultaneously exhibiting thermally activated nearest-neighbor hopping behavior. Using synchrotron grazing-incidence small-angle X-ray scattering, we show that this trend is driven by a temperature-dependent reduction in nearest-neighbor separation that is quantitatively consistent with the measured tunneling rate.

Tumor Necrosis Factor Inhibits Spread of Hepatitis C Virus Among Liver Cells, Independent From Interferons.

BACKGROUND & AIMS: Tumor necrosis factor (TNF) is an inflammatory cytokine expressed by human fetal liver cells (HFLCs) after infection with cell culture-derived hepatitis C virus (HCV). TNF has been reported to increase entry of HCV pseudoparticles into hepatoma cells and inhibit signaling by interferon alpha (IFNα), but have no effect on HCV-RNA replication. We investigated the effects of TNF on HCV infection of and spread among Huh-7 hepatoma cells and primary HFLCs. METHODS: Human hepatoma (Huh-7 and Huh-7.5) and primary HFLCs were incubated with TNF and/or recombinant IFNA2A, IFNB, IFNL1, and IFNL2 before or during HCV infection. We used 2 fully infectious HCV chimeric viruses of genotype 2A in these studies: J6/JFH (clone 2) and Jc1(p7-nsGluc2A) (Jc1G), which encodes a secreted luciferase reporter. We measured HCV replication, entry, spread, production, and release in hepatoma cells and HFLCs. RESULTS: TNF inhibited completion of the HCV infectious cycle in hepatoma cells and HFLCs in a dose-dependent and time-dependent manner. This inhibition required TNF binding to its receptor. Inhibition was independent of IFNα, IFNß, IFNL1, IFNL2, or Janus kinase signaling via signal transducer and activator of transcription. TNF reduced production of infectious viral particles by Huh-7 and HFLC, and thereby reduced the number of infected cells and focus size. TNF had little effect on HCV replicons and increased entry of HCV pseudoparticles. When cells were incubated with TNF before infection, the subsequent antiviral effects of IFNs were increased. CONCLUSIONS: In a cell culture system, we found TNF to have antiviral effects independently of, as well as in combination with, IFNs. TNF inhibits HCV infection despite increased HCV envelope glycoprotein-mediated infection of liver cells. These findings contradict those from other studies, which have reported that TNF blocks signal transduction in response to IFNs. The destructive inflammatory effects of TNF must be considered along with its antiviral effects.

Erythromelalgia involving the face.

Erythromelalgia is a rare disorder characterized by burning pain, erythema, and increased temperature typically involving the distal extremities. Although it can progress to involve the face, erythromelalgia presenting only on the face is particularly rare. This disorder is often misdiagnosed when it presents on the extremities and is even more likely to be misdiagnosed when presenting only on the face, delaying appropriate treatment and causing considerable frustration for the patient. We report a case of a 26-year-old woman with erythromelalgia that involved only the face for a number of years and was treated unsuccessfully as rosacea, seborrheic dermatitis, and contact dermatitis. She subsequently developed involvement of the ears and hands in the more typical distribution of erythromelalgia. We discuss the differential diagnosis of erythromelalgia involving the face and extremities, the proposed pathogenesis and management of the disorder, and the psychological distress this condition can cause. Even when the correct diagnosis of erythromelalgiais made, treatment is difficult, with no single therapy consistently effective.

Charge Carrier Hopping Dynamics in Homogeneously Broadened PbS Quantum Dot Solids.

Energetic disorder in quantum dot solids adversely impacts charge carrier transport in quantum dot solar cells and electronic devices. Here, we use ultrafast transient absorption spectroscopy to show that homogeneously broadened PbS quantum dot arrays (σhom2:σinh2 > 19:1, σinh/kBT < 0.4) can be realized if quantum dot batches are sufficiently monodisperse (δ ≲ 3.3%). The homogeneous line width is found to be an inverse function of quantum dot size, monotonically increasing from ∼25 meV for the largest quantum dots (5.8 nm diameter/0.92 eV energy) to ∼55 meV for the smallest (4.1 nm/1.3 eV energy). Furthermore, we show that intrinsic charge carrier hopping rates are faster for smaller quantum dots. This finding is the opposite of the mobility trend commonly observed in device measurements but is consistent with theoretical predictions. Fitting our data to a kinetic Monte Carlo model, we extract charge carrier hopping times ranging from 80 ps for the smallest quantum dots to over 1 ns for the largest, with the same ethanethiol ligand treatment. Additionally, we make the surprising observation that, in slightly polydisperse (δ ≲ 4%) quantum dot solids, structural disorder has a greater impact than energetic disorder in inhibiting charge carrier transport. These findings emphasize how small improvements in batch size dispersity can have a dramatic impact on intrinsic charge carrier hopping behavior and will stimulate further improvements in quantum dot device performance.

Allergic contact dermatitis to methylisothiazolinone in hair care products: report of a case.

Eccrine spiradenoma (ES) typically presents as a solitary tender lesion. Multiple ES is a rare variant of ES and can present in a segmental, linear, blaschkoid, or zosteriform pattern. The etiology of multiple ES is unknown, but several theories have been suggested including a multipotent stem cell origin. We report the case of a 30-year-old woman with multiple painful ES in a zosteriform pattern on the mid-back and abdomen. Skin biopsy of a representative lesion demonstrated a circumscribed tumor nodule encapsulated by a fibrous capsule with diffuse dense basophilic proliferation located in the dermis. The lesions were then excised on two separate sessions without recurrence.

ATP-dependent effector-like functions of RIG-I-like receptors.

The vertebrate antiviral innate immune system is often considered to consist of two distinct groups of proteins: pattern recognition receptors (PRRs) that detect viral infection and induce the interferon (IFN) signaling, and effectors that directly act against viral replication. Accordingly, previous studies on PRRs, such as RIG-I and MDA5, have primarily focused on their functions in viral double-stranded RNA (dsRNA) detection and consequent antiviral signaling. We report here that both RIG-I and MDA5 efficiently displace viral proteins pre-bound to dsRNA in a manner dependent on their ATP hydrolysis, and that this activity assists a dsRNA-dependent antiviral effector protein, PKR, and allows RIG-I to promote MDA5 signaling. Furthermore, truncated RIG-I/MDA5 lacking the signaling domain, and hence the IFN stimulatory activity, displaces viral proteins and suppresses replication of certain viruses in an ATP-dependent manner. Thus, this study reveals novel "effector-like" functions of RIG-I and MDA5 that challenge the conventional view of PRRs.

A serpin shapes the extracellular environment to prevent influenza A virus maturation.

Interferon-stimulated genes (ISGs) act in concert to provide a tight barrier against viruses. Recent studies have shed light on the contribution of individual ISG effectors to the antiviral state, but most have examined those acting on early, intracellular stages of the viral life cycle. Here, we applied an image-based screen to identify ISGs inhibiting late stages of influenza A virus (IAV) infection. We unraveled a directly antiviral function for the gene SERPINE1, encoding plasminogen activator inhibitor 1 (PAI-1). By targeting extracellular airway proteases, PAI-1 inhibits IAV glycoprotein cleavage, thereby reducing infectivity of progeny viruses. This was biologically relevant for IAV restriction in vivo. Further, partial PAI-1 deficiency, attributable to a polymorphism in human SERPINE1, conferred increased susceptibility to IAV in vitro. Together, our findings reveal that manipulating the extracellular environment to inhibit the last step in a virus life cycle is an important mechanism of the antiviral response.

Polymorphisms in melanoma differentiation-associated gene 5 link protein function to clearance of hepatitis C virus.

UNLABELLED: Among patients newly infected with hepatitis C virus (HCV), only 20-30% clear the infection spontaneously. In the remaining 70% the infection persists, causing chronic liver inflammation and disease. It is well established that polymorphisms in host genes, especially in components of the innate immune response, contribute to the phenomenon of spontaneous HCV clearance. Retinoic acid inducible gene-I (RIG-I)-like helicases such as melanoma differentiation-associated gene 5 (MDA-5) are cytoplasmic sensors of viral RNA that are critical for triggering innate immune responses after infection with RNA viruses. We analyzed 14 nonsynonymous single-nucleotide polymorphisms in RIG-I-like helicase-pathway-genes comparing European patients who spontaneously cleared HCV (n = 285) or had persistent infection (n = 509). We found that polymorphic haplotypes in the MDA-5 gene IFIH1 encoding histidine at position 843 and threonine at position 946 strongly correlate with the resolution of HCV infection (odds ratio [OR]: 16.23; 95% confidence interval [CI]: 3.67-71.87; P = 1.1 × 10(-6) ). Overexpression of MDA-5 genetic variants in HEK 293 cells and in a tissue culture model of HCV infection revealed that the histidine 843/threonine 946 variant leads to increased baseline and ligand-induced expression of interferon-induced genes and confers an increased ability to suppress HCV replication. CONCLUSION: These data suggest that MDA-5 plays a significant role in the defense against HCV and that polymorphisms in MDA-5 can influence the outcome of HCV infection.

Insulin for glycaemic control in acute ischaemic stroke.

BACKGROUND: People with hyperglycaemia concomitant with an acute stroke have greater mortality, stroke severity, and functional impairment when compared with those with normoglycaemia at stroke presentation. This is an update of a Cochrane Review first published in 2011. OBJECTIVES: To determine whether intensively monitoring insulin therapy aimed at maintaining serum glucose within a specific normal range (4 to 7.5 mmol/L) in the first 24 hours of acute ischaemic stroke influences outcome. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (September 2013), CENTRAL (The Cochrane Library 2013, Issue 8), MEDLINE (1950 to September 2013), EMBASE (1980 to September 2013), CINAHL (1982 to September 2013), Science Citation Index (1900 to September 2013), and Web of Science (ISI Web of Knowledge) (1993 to September 2013). We also searched ongoing trials registers and SCOPUS. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing intensively monitored insulin therapy versus usual care in adults with acute ischaemic stroke. DATA COLLECTION AND ANALYSIS: We obtained a total of 1565 titles through the literature search. Two review authors independently selected the included articles and extracted the study characteristics, study quality, and data to estimate the odds ratio (OR) and 95% confidence interval (CI), mean difference (MD) and standardised mean difference (SMD) of outcome measures. We resolved disagreements by discussion. MAIN RESULTS: We included 11 RCTs involving 1583 participants (791 participants in the intervention group and 792 in the control group). We found that there was no difference between the treatment and control groups in the outcomes of death or dependency (OR 0.99, 95% CI 0.79 to 1.23) or final neurological deficit (SMD -0.09, 95% CI -0.19 to 0.01). The rate of symptomatic hypoglycaemia was higher in the intervention group (OR 14.6, 95% CI 6.6 to 32.2). In the subgroup analyses of diabetes mellitus (DM) versus non-DM, we found no difference for the outcomes of death and disability or neurological deficit. The number needed to treat was not significant for the outcomes of death and final neurological deficit. The number needed to harm was nine for symptomatic hypoglycaemia. AUTHORS' CONCLUSIONS: After updating the results of our previous review, we found that the administration of intravenous insulin with the objective of maintaining serum glucose within a specific range in the first hours of acute ischaemic stroke does not provide benefit in terms of functional outcome, death, or improvement in final neurological deficit and significantly increased the number of hypoglycaemic episodes. Specifically, those people whose glucose levels were maintained within a tighter range with intravenous insulin experienced a greater risk of symptomatic and asymptomatic hypoglycaemia than those people in the control group.

Female gender remains an independent risk factor for poor outcome after acute nontraumatic intracerebral hemorrhage.

Objective. To study whether gender influences outcome after intracerebral hemorrhage (ICH). Methods. Cohort study of 245 consecutive adults presenting to the emergency department with spontaneous ICH from January 2006 to December 2008. Patients with subarachnoid hemorrhage, extradural hemorrhage, and recurrence of hemorrhage were excluded. Results. There were no differences noted between genders in stroke severity (NIHSS) at presentation, ICH volume, or intraventricular extension (IVE) of hemorrhage. Despite this, females had 1.94 times higher odds of having a bad outcome (modified Rankin score (mRs) ≥3) as compared to males (95% CI 1.12 to 3.3) and 1.84 times higher odds of early mortality (95% CI 1.02-3.33). analyzing known variables influencing mortality in ICH, the authors found that females did have higher serum glucose levels on arrival (P = 0.0096) and 4.2 times higher odds for a cerebellar involvement than males (95% CI 1.63-10.75). After adjusting for age, NIHSS, glucose levels, hemorrhage volume, and IVE, female gender remained an independent predictor of early mortality (P = 0.0127). Conclusions. Female gender may be an independent predictor of early mortality in ICH patients, even after adjustment for stroke severity, hemorrhage volume, IVE, serum glucose levels, and age.

The impact of blood pressure hemodynamics in acute ischemic stroke: a prospective cohort study.

OBJECTIVE: To assess relationships between blood pressure hemodynamic measures and outcomes after acute ischemic stroke, including stroke severity, disability and death. METHODS: The study cohort consisted of 189 patients who presented to our emergency department with ischemic stroke of less than 24 hours onset who had hemodynamic parameters recorded and available for review. Blood pressure (BP) was non-invasively measured at 5 minute intervals for the length of the patient's emergency department stay. Systolic BP (sBP) and diastolic BP (dBP) were measured for each patient and a differential (the maximum minus the minimum BP) calculated. Three outcomes were studied: stroke severity, disability at hospital discharge, and death at 90 days. Statistical tests used included Spearman correlations (for stroke severity), Wilcoxon test (for disability) and Cox models (for death). RESULTS: Larger differentials of either dBP (p = 0.003) or sBP (p < 0.001) were significantly associated with more severe strokes. A greater dBP (p = 0.019) or sBP (p = 0.036) differential was associated with a significantly worse functional outcome at hospital discharge. Those patients with larger differentials of either dBP (p = 0.008) or sBP (0.007) were also significantly more likely to be dead at 90 days, independently of the basal BP. CONCLUSION: A large differential in either systolic or diastolic blood pressure within 24 hours of symptom onset in acute ischemic stroke appears to be associated with more severe strokes, worse functional outcome and early death.

Spontaneous retroperitoneal hematoma: etiology, characteristics, management, and outcome.

BACKGROUND: Spontaneous retroperitoneal hematoma (SRH) can be fatal, requiring immediate recognition and intervention. Current literature is limited, providing little direction in patient care. OBJECTIVE: To describe clinical characteristics of patients with SRH during an 8-year period. METHODS: Observational cohort study of all consecutive patients 18 years and older with SRH from January 2000 to December 2007. SRH was defined as unrelated to invasive procedures, surgery, trauma, or abdominal aortic aneurysm. RESULTS: Of 346 patients screened, 89 were eligible. Median age was 72 years; 56.2% were male. Overall, 66.3% were anticoagulated: 41.6% on warfarin, 30.3% heparin, and 11.2% low-molecular-weight heparin; 30.3% were on antiplatelet therapy; 16.5% were taking both anticoagulant and antiplatelet medications; 15.3% were taking neither. Primary presentation to the Emergency Department was seen in 36%; 64% developed SRH during inpatient anticoagulation therapy. The most common symptom was pain: abdominal (67.5%), leg (23.8%), hip (22.5%), and back (21.3%); 10.1% were misdiagnosed upon their initial encounter. Computed tomography (CT) was performed in 98.8%, ultrasound in 22.1%, and magnetic resonance imaging in 3.5%. Of all subjects, 40.4% were managed in an intensive care unit; 24.7% underwent interventional radiology (IR) procedures and 6.7% surgical evacuation; 75.3% received blood transfusion. Mortality was 5.6% within 7 days, 10.1% within 30 days, and 19.1% within 6 months. CONCLUSIONS: SRH is uncommon but potentially lethal, with a non-specific presentation that can lead to misdiagnosis. One-third of the cohort was not taking anticoagulants. CT was effective at identification. Most patients received aggressive management with transfusion or IR procedures.

Cardioembolic but not other stroke subtypes predict mortality independent of stroke severity at presentation.

Introduction. Etiology of acute ischemic stroke (AIS) is known to significantly influence management, prognosis, and risk of recurrence. Objective. To determine if ischemic stroke subtype based on TOAST criteria influences mortality. Methods. We conducted an observational study of a consecutive cohort of patients presenting with AIS to a single tertiary academic center. Results. The study population consisted of 500 patients who resided in the local county or the surrounding nine-county area. No patients were lost to followup. Two hundred and sixty one (52.2%) were male, and the mean age at presentation was 73.7 years (standard deviation, SD = 14.3). Subtypes were as follows: large artery atherosclerosis 97 (19.4%), cardioembolic 144 (28.8%), small vessel disease 75 (15%), other causes 19 (3.8%), and unknown 165 (33%). One hundred and sixty patients died: 69 within the first 30 days, 27 within 31-90 days, 29 within 91-365 days, and 35 after 1 year. Low 90-, 180-, and 360-day survival was seen in cardioembolic strokes (67.1%, 65.5%, and 58.2%, resp.), followed for cryptogenic strokes (78.0%, 75.3%, and 71.1%). Interestingly, when looking into the cryptogenic category, those with insufficient information to assign a stroke subtype had the lowest survival estimate (57.7% at 90 days, 56.1% at 180 days, and 51.2% at 1 year). Conclusion. Cardioembolic ischemic stroke subtype determined by TOAST criteria predicts long-term mortality, even after adjusting for age and stroke severity.

Insulin for glycaemic control in acute ischaemic stroke.

BACKGROUND: Patients with hyperglycaemia concomitant with an acute stroke have greater stroke severity and greater functional impairment when compared to those with normoglycaemia at stroke presentation. OBJECTIVES: To determine whether maintaining serum glucose within a specific normal range (4 to 7.5 mmol/L) in the first 24 hours of acute ischaemic stroke influences outcome. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (June 2010), CENTRAL (The Cochrane Library 2010, Issue 2), MEDLINE (1950 to June 2010), EMBASE (1980 to June 2010), CINAHL (1982 to June 2010), Science Citation Index (1900 to June 2010), and Web of Science (ISI Web of Knowledge) (1993 to June 2010). In an effort to identify further published, unpublished and ongoing trials we searched ongoing trials registers and SCOPUS. SELECTION CRITERIA: Eligible studies were randomised controlled trials comparing intensively monitored insulin therapy versus usual care in adult patients with acute ischaemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the study characteristics, study quality, and data to estimate the odds ratio (OR) and 95% confidence interval (CI), mean difference (MD) and standardised mean difference (SMD) of outcome measures. MAIN RESULTS: We included seven trials involving 1296 participants (639 participants in the intervention group and 657 in the control group). We found that there was no difference between treatment and control groups in the outcome of death or disability and dependence (OR 1.00, 95% CI 0.78 to 1.28) or final neurological deficit (SMD -0.12, 95% CI -0.23 to 0.00). The rate of symptomatic hypoglycaemia was higher in the intervention group (OR 25.9, 95% CI 9.2 to 72.7). In the subgroup analyses of diabetes mellitus (DM) versus non-DM, we found no difference for the outcomes of death and dependency or neurological deficit. AUTHORS' CONCLUSIONS: With the current evidence, we found that the administration of intravenous insulin with the objective of maintaining serum glucose within a specific range in the first hours of acute ischaemic stroke does not provide benefit in terms of functional outcome, death, or improvement in final neurological deficit and significantly increased the number of hypoglycaemic episodes. Specifically, those who were maintained within a more tight range of glycaemia with intravenous insulin experienced a greater risk of symptomatic and asymptomatic hypoglycaemia than those individuals in the control group.