Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation.

Saturated fatty acids (FA) exert adverse health effects and are more likely to cause insulin resistance and type 2 diabetes than unsaturated FA, some of which exert protective and beneficial effects. Saturated FA, but not unsaturated FA, activate Jun N-terminal kinase (JNK), which has been linked to obesity and insulin resistance in mice and humans. However, it is unknown how saturated and unsaturated FA are discriminated. We now demonstrate that saturated FA activate JNK and inhibit insulin signaling through c-Src activation. FA alter the membrane distribution of c-Src, causing it to partition into intracellular membrane subdomains, where it likely becomes activated. Conversely, unsaturated FA with known beneficial effects on glucose metabolism prevent c-Src membrane partitioning and activation, which are dependent on its myristoylation, and block JNK activation. Consumption of a diabetogenic high-fat diet causes the partitioning and activation of c-Src within detergent insoluble membrane subdomains of murine adipocytes.

Long-Term Patient-Reported Outcomes of Visual Field Defects and Compensatory Mechanisms in Patients After Cerebral Hemispherectomy.

BACKGROUND: In cases of intractable epilepsy resistant to drug therapy, hemispherectomy is often the only treatment option to mitigate seizures; however, the true long-term subjective visual outcomes are relatively unexplored. In this study, we sought to determine and characterize patient-reported visual function years after hemispherectomy. METHODS: This was an observational study conducted on a large cohort of children with seizure disorder treated with cerebral hemispherectomy. An online survey was sent to parents with questions to assess subjective visual function with a variety of questions from presence of visual field defects after hemispherectomy, to improvement over time, compensatory mechanisms used, and development of strabismus. RESULTS: This survey was emailed to 248 parents of previously evaluated children who agreed to be re-surveyed, 48 (20%) of which responded. The average age at hemispherectomy was approximately 5 (±4) years, and the average time after hemispherectomy was 7 (±5) years. Thirty-nine patients (81%) were seizure-free after 1 surgery and 85% (n = 41) were seizure-free after ≥1 surgeries. Thirty-four (71%) experienced a visual field defect after surgery, but 25 (52%) experienced subjective improvement over time. Thirty-eight (79%) used compensatory mechanisms, such as head tilting, with 16 (33%) patients experiencing subjective improvement over time. Twenty-seven (56%) patients experienced a decrease in visual acuity after surgery with 12 (25%) experiencing subjective improvement over time. CONCLUSION: In a large cohort examining patient-reported visual outcomes years after hemispherectomy, most patients experienced strabismus and/or visual field defects. However, more than half reported improvements and compensatory mechanisms (exotropic strabismus and ipsilateral esotropic strabismus) over time, presumably to enhance visual field function. By exploring subjective visual and cognitive function, this paper uniquely characterizes patient-reported improvements over time, and provides motivation for larger longitudinal studies using more quantitative measures of visual function and improvement after hemispherectomy.

Gastrointestinal Disorders and Risk of First-Ever Ischemic Stroke.

BACKGROUND AND PURPOSE: Recent studies suggest that alteration of the normal gut microbiome contributes to atherosclerotic burden and cardiovascular disease. While many gastrointestinal diseases are known to cause disruption of the normal gut microbiome in humans, the clinical impact of gastrointestinal diseases on subsequent cerebrovascular disease remains unknown. We conducted an exploratory analysis evaluating the relationship between gastrointestinal diseases and ischemic stroke. METHODS: We performed a retrospective cohort study using claims between 2008 and 2015 from a nationally representative 5% sample of Medicare beneficiaries. We included only beneficiaries ≥66 years of age. We used previously validated diagnosis codes to ascertain our primary outcome of ischemic stroke. In an exploratory manner, we categorized gastrointestinal disorders by anatomic location, disease chronicity, and disease mechanism. We used Cox proportional hazards models to examine associations of gastrointestinal disorder categories and ischemic stroke with adjustment for demographics and established vascular risk factors. RESULTS: Among a mean of 1 725 246 beneficiaries in each analysis, several categories of gastrointestinal disorders were associated with an increased risk of ischemic stroke after adjustment for established stroke risk factors. The most notable positive associations included disorders of the stomach (hazard ratio, 1.17 [95% CI, 1.15-1.19]) and functional (1.16 [95% CI, 1.15-1.17]), inflammatory (1.13 [95% CI, 1.12-1.15]), and infectious gastrointestinal disorders (1.13 [95% CI, 1.12-1.15]). In contrast, we found no associations with stroke for diseases of the anus and rectum (0.97 [95% CI, 0.94-1.00]) or neoplastic gastrointestinal disorders (0.97 [95% CI, 0.94-1.00]). CONCLUSIONS: In exploratory analyses, several categories of gastrointestinal disorders were associated with an increased risk of future ischemic stroke after adjustment for demographics and established stroke risk factors.

Associations between cerebrovascular risk factors and parkinson disease.

OBJECTIVE: To determine whether cerebrovascular risk factors are associated with subsequent diagnoses of Parkinson disease, and whether these associations are similar in magnitude to those with subsequent diagnoses of Alzheimer disease. METHODS: This was a retrospective cohort study using claims data from a 5% random sample of Medicare beneficiaries from 2008 to 2015. The exposures were stroke, atrial fibrillation, coronary disease, hyperlipidemia, hypertension, sleep apnea, diabetes mellitus, heart failure, peripheral vascular disease, chronic kidney disease, chronic obstructive pulmonary disease, valvular heart disease, tobacco use, and alcohol abuse. The primary outcome was a new diagnosis of idiopathic Parkinson disease. The secondary outcome was a new diagnosis of Alzheimer disease. Marginal structural Cox models adjusting for time-dependent confounding were used to characterize the association between exposures and outcomes. We also evaluated the association between cerebrovascular risk factors and subsequent renal colic (negative control). RESULTS: Among 1,035,536 Medicare beneficiaries followed for a mean of 5.2 years, 15,531 (1.5%) participants were diagnosed with Parkinson disease and 81,974 (7.9%) were diagnosed with Alzheimer disease. Most evaluated cerebrovascular risk factors, including prior stroke (hazard ratio = 1.55; 95% confidence interval = 1.39-1.72), were associated with the subsequent diagnosis of Parkinson disease. The magnitudes of these associations were similar, but attenuated, to the associations between cerebrovascular risk factors and Alzheimer disease. Confirming the validity of our analytical model, most cerebrovascular risk factors were not associated with the subsequent diagnosis of renal colic. INTERPRETATION: Cerebrovascular risk factors are associated with Parkinson disease, an effect comparable to their association with Alzheimer disease. ANN NEUROL 2019;86:572-581.

National Trends in Hospitalizations for Stroke Associated With Infective Endocarditis and Opioid Use Between 1993 and 2015.

Background and Purpose- There has been a recent sharp rise in opioid-related deaths in the United States. Intravenous opioid use can lead to infective endocarditis (IE) which can result in stroke. There are scant data on recent trends in this neurological complication of opioid abuse. We hypothesized that increasing opioid abuse has led to a higher incidence of stroke associated with IE and opioid use. Methods- We used the 1993 to 2015 releases of the National Inpatient Sample and validated International Classification of Diseases, Ninth Revision, Clinical Modification codes ( ICD-9-CM) to identify hospitalizations with the combination of opioid abuse, IE, and stroke (defined as ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage). Survey weights provided by the National Inpatient Sample were used to calculate nationally representative estimates and population estimates from the United States. Census data were used to calculate annual hospitalization rates per 10 million person-years. Joinpoint regression was used to assess trends. Results- From 1993 through 2015, there were 5283 hospitalizations with stroke associated with IE and opioid use. Across this period, the rate of such hospitalizations increased from 2.4 (95% CI, 0.5-4.3) to 18.8 (95% CI, 14.4-23.3) per 10 million US residents. Joinpoint regression detected 2 segments: no significant change in the hospitalization rate was apparent from 1993 to 2008 (annual percentage change, 1.9%; 95% CI, -2.2% to 6.1%), and then rates significantly increased from 2008 to 2015 (annual percentage change, 20.3%; 95% CI, 10.5%-30.9%), most dramatically in non-Hispanic white patients in the Northeastern and Southern United States. Conclusions- US hospitalization rates for stroke associated with IE and opioid use were stable for ≈2 decades but then sharply increased starting in 2008, coinciding with the emergence of the opioid epidemic.

Association Between Intravenous Thrombolysis and Anaphylaxis Among Medicare Beneficiaries With Acute Ischemic Stroke.

Background and Purpose- Allergic reactions, including anaphylaxis, can sometimes occur after intravenous thrombolysis in patients with acute ischemic stroke. However, it remains unclear whether patients with stroke who receive thrombolytic agents face a higher risk of anaphylaxis than those who do not receive thrombolytics. Methods- We performed a retrospective cohort study using inpatient and outpatient claims between 2008 and 2015 from a nationally representative 5% sample of Medicare beneficiaries. We included patients who were ≥65 years old and hospitalized with acute ischemic stroke, defined by validated International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Our exposure was treated with an intravenous thrombolytic agent during the index hospitalization (International Classification of Diseases, Ninth Revision, Clinical Modification code 99.10). Our primary outcome was anaphylaxis, defined using an accepted International Classification of Diseases, Ninth Revision, Clinical Modification code algorithm (989.5, 995.0-4, 995.6x, E905, E905.3, E905.5, or E905.8-9). A secondary outcome was anaphylactic shock (995.0 or 995.6x). Multiple logistic regression was used to evaluate the association between intravenous thrombolysis and anaphylaxis after adjustment for demographics, vascular risk factors, the Charlson comorbidity index, exposure to intravenous contrast dye, treatment with mechanical thrombectomy, and history of allergic reactions. Results- Among 66 989 patients with stroke, the 3176 (4.7%) who underwent intravenous thrombolysis more often had atrial fibrillation (47.7% versus 37.4%) and more often received intravenous contrast dye (44.3% versus 21.9%) but were otherwise similar in terms of demographics and comorbidities. Anaphylaxis developed in 17 (0.54%; 95% CI, 0.31%-0.86%) patients who received intravenous thrombolysis versus 45 (0.07%; 95% CI, 0.05%-0.09%) who did not. After adjustment for demographics, comorbidities, contrast dye, mechanical thrombectomy, and history of allergies, there was a significant association between receipt of intravenous thrombolysis and anaphylaxis (odds ratio, 7.8; 95% CI, 4.3-13.9). We found a similar association for anaphylactic shock. Conclusions- Although a rare occurrence, the risk of anaphylaxis among patients with acute ischemic stroke was significantly higher among those who received intravenous thrombolysis.

Association Between Heart Transplantation and Subsequent Risk of Stroke Among Patients With Heart Failure.

Background and Purpose- It is uncertain whether heart transplantation decreases the risk of stroke. The objective of our study was to determine whether heart transplantation is associated with a decreased risk of subsequent stroke among patients with heart failure awaiting transplantation. Methods- We performed a retrospective cohort study using administrative data from New York, California, and Florida between 2005 and 2015. Individuals with heart failure awaiting heart transplantation were identified using previously validated International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for heart failure in combination with code V49.83 for awaiting organ transplant status. Individuals with prior stroke were excluded. Our primary exposure variable was heart transplantation, modeled as a time-varying covariate and defined by procedure code 37.51. The primary outcome was stroke, defined as the composite of ischemic and hemorrhagic stroke. Survival statistics were used to calculate stroke incidence, and Cox proportional hazards analysis was used to determine the association between heart transplantation and stroke while adjusting for demographics, stroke risk factors, Elixhauser comorbidities, and implantation of a left ventricular assist device. Results- We identified 7848 patients with heart failure awaiting heart transplantation, of whom 1068 (13.6%) underwent heart transplantation. During a mean follow-up of 2.7 years, we identified 428 strokes. The annual incidence of stroke was 0.7% (95% CI, 0.5%-1.0%) after heart transplantation versus 2.4% (95% CI, 2.2%-2.6%) among those awaiting heart transplantation. After adjustment for potential confounders, heart transplantation was associated with a lower risk of stroke (hazard ratio, 0.4; 95% CI, 0.2-0.6). Conclusions- Heart transplantation is associated with a decreased risk of stroke among patients with heart failure awaiting transplantation.

Effect of A Randomized trial of Unruptured Brain Arteriovenous Malformation on Interventional Treatment Rates for Unruptured Arteriovenous Malformations.

BACKGROUND: In 2013, investigators from A Randomized Trial of Unruptured Brain Arteriovenous Malformations (AVM; ARUBA) reported that interventions to obliterate unruptured AVMs caused more morbidity and mortality than medical management. OBJECTIVE: We sought to determine whether interventions for unruptured AVM decreased after publication of ARUBA results. METHODS: We used the Nationwide Readmissions Database to assess trends in interventional AVM management in patients ≥18 years of age from 2010 through 2015. Unruptured brain AVMs were identified using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code 747.81 and excluding any patient with a diagnosis of intracranial hemorrhage. Our primary outcome was interventional AVM treatment, identified using ICD-9-CM procedure codes for surgical resection, endovascular therapy, and stereotactic radiosurgery. Join-point regression was used to assess trends in the incidence of interventional AVM management among adults from 2010 through 2015. RESULTS: There was no significant U.S. population level change in unruptured brain AVM intervention rates before versus after ARUBA (p = 0.59), with the incidence of AVM intervention ranging from 8.0 to 9.2 per 10 million U.S. residents before the trial publication to 7.7-8.3 per 10 million afterwards. CONCLUSIONS: In a nationally representative sample, we found no change in rates of interventional unruptured AVM management after publication of the ARUBA trial results.

Cyclodestructive procedures for refractory glaucoma.

BACKGROUND: Cyclodestructive procedures are often used in patients with refractory glaucoma who have failed to achieve lower intraocular pressure (IOP) from filtration procedures and maximal medical therapy. Destruction of the ciliary body helps to lower IOP by reducing aqueous humor formation. Of the many types of cyclodestructive procedures, laser cyclophotocoagulation (CPC) has become the most common surgical method for reducing aqueous inflow. Options for CPC are wide-ranging: they can be performed using a neodymium:yttrium-aluminum-garnet (Nd:YAG) or diode laser and laser energy can be delivered by either the contact or non-contact method. Another cyclodestructive procedure is endoscopic cyclophotocoagulation (ECP), which the ophthalmologist can use selectively to target the ciliary epithelium and ablate ciliary body tissue. There is debate regarding which cyclodestructive method is best and how they compare to other glaucoma surgeries. OBJECTIVES: To assess the relative effectiveness and safety of cyclodestructive procedures compared with other procedures in people with refractory glaucoma of any type and to assess the relative effectiveness and safety of individual cyclodestructive procedures compared with each other. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 9); Ovid MEDLINE; Embase.com; PubMed; LILACS BIREME; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 21 September 2018. SELECTION CRITERIA: We included randomized controlled trials or quasi-randomized trials in which participants underwent a secondary procedure for refractory glaucoma. We included trials with any laser type, route of administration, and laser settings. The primary comparison was any cyclodestructive procedure versus another glaucoma treatment, and the secondary comparisons were individual cyclodestructive procedures versus another cyclodestructive procedure. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed the titles and abstracts from the database searches, and after retrieving the full-text reports of those that were potentially relevant, classified the full-text articles as included or excluded. Two review authors independently extracted data from the included studies and assessed the risk of bias. Discrepancies were resolved by discussion or by consultation with a third review author when necessary. MAIN RESULTS: We included five trials reporting data for 330 eyes (326 participants). One study to had a low risk of bias for most domains and the other studies had an overall unclear risk of bias. This review includes four different comparisons: 1) ECP versus Ahmed implant, 2) micropulse CPC versus continuous-wave CPC; 3) CPC with a diode versus Nd:YAG laser; and 4) CPC with an Nd:YAG laser emitting 8J versus 4J.No study reported data for our primary outcome, change from baseline in pain severity as reported by the participant or change in number of pain medications.For our primary comparison, we included one trial that compared ECP with the Ahmed implant. At 12-month follow-up, the mean difference (MD) in IOPs between groups was -1.14 mmHg (95% confidence interval (CI) -4.21 to 1.93; 58 participants; low-certainty evidence (LCE)). At 24 months postintervention, we found very LCE suggesting that visual acuity may be better among participants in the ECP group than in the Ahmed implant group (MD -0.24 logMAR, 95% CI -0.52 to 0.04; 54 participants), and the difference in the mean number of glaucoma medications used by participants in each group was unclear (MD -0.50, 95% CI -1.17 to 0.17; 54 participants; very LCE). Reported adverse events in the ECP group (34 participants) were one case each of hypotony, phthisis bulbi, retinal detachment, and choroidal detachment; in the Ahmed implant group (34 participants) there was one case of endophthalmitis, two cases of retinal detachment, and six cases of choroidal detachment.Three types of comparisons from four included studies provided data for our secondary comparisons. In the study that compared micropulse with continuous-wave CPC, median IOP was reported to be similar between the two groups at all time points. At 18 months postintervention, the median number of IOP-lowering medications was reduced from two to one in both groups. One participant in the micropulse and two in the continuous group exhibited worsened visual acuity. One case of prolonged inflammation was seen in the micropulse group (23 participants). Seven cases of prolonged inflammation, five cases of hypotony, and one case of phthisis bulbi were seen in the continuous group (23 participants).Two studies compared CPC using a semiconductor diode versus an Nd:YAG laser. At 12 months postintervention, the MD in IOP was 1.02 mmHg (95% CI -1.49 to 3.53) in one study (LCE). The second study did not report mean IOP beyond three months of follow-up. Neither study reported the mean change in best-corrected visual acuity or number of glaucoma medications. Both studies reported hypotony as an adverse event in three participants in each study.One study compared different energy settings of the same Nd:YAG laser. At 12-month follow-up, visual acuity was unchanged or improved in 21 of 33 participants in the 8J group and 20 of 27 participants in the 4J group (risk ratio 0.86, 95% CI 0.61 to 1.21; very LCE). More participants in the 8J group reduced the number of medications taken compared with the 4J group (RR 1.49, 95% CI 0.76 to 2.91; 50 participants; very low-certainty evidence). The presence of fibrin or hyphema were seen in five participants who received 8J and none who received 4J. There was a severe anterior chamber reaction in 11 of 26 (42%) participants who received 8J of energy and 2 of 21 (10%) participants who received 4J of energy. AUTHORS' CONCLUSIONS: Evidence from five studies included in this review was inconclusive as to whether cyclodestructive procedures for refractory glaucoma result in better outcomes and fewer complications than other glaucoma treatments, and whether one type of cyclodestructive procedure is better than another. The most commonly reported adverse events across all five studies were hypotony and phthisis bulbi. Large, well-designed randomized controlled trials are needed. Patient-reported outcomes such as pain and quality of life should be considered as primary outcomes or important secondary outcomes of future trials.

Children bouncing to the emergency department: Changes in trampoline injury patterns.

AIM: To compare trampoline injuries and injury costs sustained at a commercial trampoline park versus private homes presenting to a major Australian children's hospital over a 12-month period. METHODS: Children presenting with a trampoline injury to the paediatric emergency department in 2015 were identified using a keyword search of triage information. A comparison of injuries sustained at a commercial trampoline park and private homes was performed. RESULTS: A total of 392 children presented with injuries, and the majority of injuries (68.9%) occurred at a private home; 19.4% were from a commercial trampoline park. Significant differences were seen between patients from a private home and commercial park for median age (5.6 vs. 12.8 years; P < 0.001), gender (48.2 vs. 61.8% female; P = 0.03) and season of injury. Of the injuries, 27.3% occurred when children fell off the trampoline, and fractures (39.5%) were the most common injury; 17.4% required hospital admission, and 12.8% required surgical intervention. Commercial park injuries had a significantly longer median length of stay (37.4 vs. 22.8 h; P = 0.03). The estimated total acute cost for these trampoline injuries in 1 year was $546 786. Commercial trampoline park injuries accounted for 21.7% of the estimated cost and private homes for 68.2%. CONCLUSIONS: Paediatric trampoline injuries remain a common source of hospital presentation and admission, despite the introduction of a Voluntary Australian Standard. Paediatric trampoline injuries usually occur in private homes; however, the increasing popularity of commercial trampoline parks contributes to a change in the profile of trampoline injuries. Commercial park injuries were more expensive to treat.

The Risk of Takotsubo Cardiomyopathy in Acute Neurological Disease.

BACKGROUND: Case series have reported reversible left ventricular dysfunction, also known as stress cardiomyopathy or Takotsubo cardiomyopathy (TCM), in the setting of acute neurological diseases such as subarachnoid hemorrhage. The relative associations between various neurological diseases and Takotsubo remain incompletely understood. METHODS: We performed a cross-sectional study of all adults in the National Inpatient Sample, a nationally representative sample of US hospitalizations, from 2006 to 2014. Our exposures of interest were primary diagnoses of acute neurological disease, defined by ICD-9-CM diagnosis codes. Our outcome was a diagnosis of TCM. Binary logistic regression models were used to examine the associations between our pre-specified neurological diagnoses and TCM after adjustment for demographics. RESULTS: Among acute neurological diagnoses, the strongest associations were seen with subarachnoid hemorrhage (odds ratio [OR] 11.7; 95% confidence interval [CI] 10.2-13.4), status epilepticus (OR 4.9; 95% CI 3.7-6.3), and seizures (OR 1.3; 95% CI 1.1-1.5). In a sensitivity analysis including secondary diagnoses of acute neurological diagnoses, associations were also seen with transient global amnesia (OR 2.3; 95% CI 1.5-3.6), meningoencephalitis (OR 2.1; 95% CI 1.7-2.5), migraine (OR 1.7; 95% CI 1.5-1.8), intracerebral hemorrhage (OR 1.3; 95% CI 1.1-1.5), and ischemic stroke (OR 1.2; 95% CI 1.1-1.3). In addition, female sex was strongly associated with Takotsubo (OR 5.1; 95% CI 4.9-5.4). CONCLUSION: TCM appears to be associated with varying degrees with several acute neurological diseases besides subarachnoid hemorrhage.

Specialty Classifications of Physicians Who Provide Neurocritical Care in the United States.

BACKGROUND: We sought to characterize the specialty classification of US physicians who provide critical care for neurological/neurosurgical disease. METHODS: Using inpatient claims between 2009 and 2015 from a nationally representative 5% sample of Medicare beneficiaries, we selected hospitalizations for neurological/neurosurgical diseases with potential to result in life-threatening manifestations requiring critical care. Using Current Procedural Terminology® codes, we determined the medical specialty of providers submitting critical care claims, and, using National Provider Identifier numbers, we merged in data from the United Council for Neurologic Subspecialties (UCNS) to determine whether the provider was a UCNS diplomate in neurocritical care. We defined providers with a clinical neuroscience background as neurologists, neurosurgeons, and/or UCNS diplomates in neurocritical care. We defined neurocritical care service as a critical care claim with a qualifying neurological/neurosurgical diagnosis in patients with a relevant primary hospital discharge diagnosis and ≥ 3 total critical care claims, excluding claims from the first day of hospitalization since these were mostly emergency-department claims. Our findings were reported using descriptive statistics with exact confidence intervals (CI). RESULTS: Among 1,952,305 Medicare beneficiaries, we identified 99,937 hospitalizations with at least one claim for neurocritical care. In our primary analysis, neurologists accounted for 28.0% (95% CI, 27.5-28.5%) of claims, neurosurgeons for 3.7% (95% CI, 3.5-3.9%), UCNS-certified neurointensivists for 25.8% (95% CI, 25.3-26.3%), and providers with any clinical neuroscience background for 42.8% (95% CI, 42.2-43.3%). The likelihood of management by physicians with a clinical neuroscience background increased proportionally with patients' county-level socioeconomic status and such providers were 3 times more likely to be based at an academic medical center than other physicians who billed for critical care in our sample (odds ratio, 2.9; 95% CI, 1.1-8.1). CONCLUSIONS: Physicians with a dedicated clinical neuroscience background accounted for less than half of neurocritical care service in US Medicare beneficiaries.

Clinical Impact of Thrombophilia Screening in Young Adults with Ischemic Stroke.

OBJECTIVE: We evaluated the ability of genetic and serological testing to diagnose clinically relevant thrombophilias in young adults with ischemic stroke. METHODS: We performed a retrospective cohort study of patients aged 18-65 years diagnosed with acute ischemic stroke at a comprehensive stroke center between 2011 and 2015 with laboratory testing for thrombophilia. The primary outcome was any positive thrombophilia screening test. The secondary outcome was a change in clinical management based on thrombophilia testing results. Logistic regression was used to assess whether the prespecified risk factors of age, sex, prior venous thromboembolism, family history of stroke, stroke subtype, and presence of patent foramen ovale were associated with outcomes. RESULTS: Among 196 young ischemic stroke patients, at least 1 positive thrombophilia test was identified in 85 patients (43%; 95% CI, 36%-51%) and 16 (8%; 95% CI, 5%-13%) had a resultant change in management. Among 111 patients with cryptogenic strokes, 49 (44%) had an abnormal thrombophilia test and 9 (8%) had a change in management. After excluding cases of isolated hyperhomocysteinemia or methylenetetrahydrofolate reductase or Factor V Leiden gene mutation heterozygosity, the proportion of patients with an abnormal thrombophilia screen decreased to 24%. Prespecified risk factors were not significantly associated with positive thrombophilia testing or a change in management. CONCLUSIONS: Two-of-five young patients with ischemic stroke who underwent thrombophilia screening at our institution had at least 1 positive test but only one-in-twelve had a resultant change in clinical management. Neither cryptogenic stroke subtype nor other studied clinical factors were associated with a prothrombotic state.

Temporal Trends in the Use of Acute Recanalization Therapies for Ischemic Stroke in Patients with Cancer.

OBJECTIVE: We sought to characterize the US nationwide temporal trends in recanalization therapy utilization for ischemic stroke among patients with and without cancer. METHODS: We identified all acute ischemic stroke (AIS) hospitalizations in the National Inpatient Sample from January 1, 1998 to September 30, 2015. The primary exposure was solid or hematologic cancer. The primary outcome was use of intravenous thrombolysis. The secondary outcome was use of endovascular therapy (EVT). RESULTS: Among 9,508,804 AIS hospitalizations, 503,510 (5.3%) involved cancer patients. Intravenous thrombolysis use among ischemic stroke patients with cancer increased from .01% (95% confidence interval [CI], .00%-.02%) in 1998 to 4.91% (95% CI, 4.33%-5.48%) in 2015, whereas intravenous thrombolysis use among ischemic stroke patients without cancer increased from .02% (95% CI, .01%-.02%) in 1998 to 7.22% (95% CI, 6.98%-7.45%) in 2015. The demographic- and comorbidity-adjusted odds ratio/year of receiving intravenous thrombolysis was similar in patients with cancer (1.21; 95% CI, 1.20-1.23) versus those without (1.20; 95% CI, 1.19-1.21). EVT use among ischemic stroke patients with cancer increased from .05% (95% CI, .02%-.07%) in 2006 to 1.90% (95% CI, 1.49%-2.31%) in 2015, whereas EVT use among ischemic stroke patients without cancer increased from .09% (95% CI, .00%-.18%) in 2006 to 1.88% (95% CI, 1.68%-2.09%) in 2015. CONCLUSIONS: Among 9.5 million AIS hospitalizations, patients with cancer received intravenous thrombolysis about two thirds as often as patients without cancer. This difference persisted over time despite increased utilization in both groups. EVT utilization was similar between cancer and non-cancer AIS patients.

Association Between Unruptured Intracranial Aneurysms and Downstream Stroke.

Background and Purpose- Case reports suggest that unruptured intracranial aneurysms may serve as a nidus for thrombus formation and downstream embolic stroke. However, few data exist to support an association between unruptured aneurysms and ischemic stroke. Methods- We conducted a within-subjects case-control study of acute ischemic stroke patients prospectively enrolled in the Cornell Acute Stroke Academic Registry who had magnetic resonance imaging of the brain and arterial imaging of the head within 14 days of admission. Reviewers blinded to the study hypothesis ascertained the presence of aneurysms from the neuroradiologist's clinical report of the arterial imaging findings. McNemar test for paired data was used to compare the prevalence of unruptured aneurysms ipsilateral versus contralateral to the side of anterior circulation infarcts. Aneurysms of the anterior communicating artery or in the posterior circulation were not counted in the analysis. Results- Among 2116 patients registered in the Cornell Acute Stroke Academic Registry during 2011 to 2016, 1541 met our inclusion criteria, of whom 176 (11.4%; 95% CI, 9.8-13.0%) had an intracranial aneurysm. The prevalence of aneurysms did not differ on the side ipsilateral versus contralateral to the infarction (risk ratio [RR], 1.2; 95% CI, 0.9-1.5). There was no significant association between aneurysms and ipsilateral stroke in secondary analyses of the 1244 patients with stroke in a single anterior circulation territory (RR, 1.2; 95% CI, 0.8-1.9), the 619 patients with cryptogenic stroke (RR, 1.4; 95% CI, 0.9-2.0), or the 485 patients with cryptogenic stroke in a single anterior circulation territory (RR, 1.7; 95% CI, 0.8-3.3). Results were unchanged when counting only aneurysms >3 mm (RR, 1.2; 95% CI, 0.8-1.9) or 5 mm in diameter (RR, 1.2; 95% CI, 0.9-1.5). Conclusions- Contrary to our hypothesis, we found no significant association between unruptured intracranial aneurysms and ipsilateral ischemic stroke.

Incidence of Atrial Fibrillation in Patients With Recent Ischemic Stroke Versus Matched Controls.

Background and Purpose- It is unclear whether atrial fibrillation/flutter (AF) newly diagnosed after ischemic stroke represents a preexisting risk factor that led to stroke, an arrhythmia triggered by poststroke autonomic dysfunction, or an incidental finding. Methods- We compared AF incidence after hospitalizations for ischemic stroke, hemorrhagic stroke, and nonstroke conditions using inpatient and outpatient claims between 2008 and 2015 from a nationally representative 5% sample of Medicare beneficiaries. We used validated International Classification of Diseases, Ninth Revision, Clinical Modification ( ICD-9-CM) codes to identify AF-free patients hospitalized with ischemic or hemorrhagic stroke and matched them in a 1:1 ratio by age, sex, race, calendar year, vascular risk factors, and Charlson comorbidities. We then matched the combined stroke cohort in a 1:1 ratio to patients hospitalized for nonstroke diagnoses. We used survival statistics and Cox regression to compare postdischarge AF incidence among groups. Results- We matched 2580 patients with ischemic stroke, 2580 with hemorrhagic stroke, and 5160 patients with other conditions. The annual postdischarge AF incidence was 3.4% (95% CI, 3.1%-3.7%) after ischemic stroke, 2.2% (95% CI, 1.9%-2.4%) after hemorrhagic stroke, and 2.9% (95% CI, 2.6%-3.1%) after nonstroke hospitalization. Ischemic stroke was associated with a somewhat higher risk of AF than hemorrhagic stroke (hazard ratio, 1.5; 95% CI, 1.3-1.8) or nonstroke conditions (hazard ratio, 1.2; 95% CI, 1.1-1.3). The latter association attenuated in sensitivity analyses limiting the outcome to AF diagnoses made by cardiologists (hazard ratio, 1.1; 95% CI, 0.8-1.5) or limiting the outcome to a minimum of 2 AF claims on separate dates (hazard ratio, 1.2; 95% CI, 1.0-1.5; P=0.09). Conclusions- New diagnoses of AF were more common after hospitalization for ischemic stroke than after hospitalization for hemorrhagic stroke or nonstroke conditions, but all hospitalized patients had a substantial incidence of new AF diagnoses after discharge and differences were attenuated when using more stringent definitions.

Risk of seizures and status epilepticus in older patients with liver disease.

OBJECTIVE: Seizures can be provoked by systemic diseases associated with metabolic derangements, but the association between liver disease and seizures remains unclear. METHODS: We performed a retrospective cohort study using inpatient and outpatient claims between 2008 and 2015 from a nationally representative 5% sample of Medicare beneficiaries. The primary exposure variable was cirrhosis, and the secondary exposure was mild, noncirrhotic liver disease. The primary outcome was seizure, and the secondary outcome was status epilepticus. Diagnoses were ascertained using validated International Classification of Diseases, Ninth Edition, Clinical Modification codes. Survival statistics were used to calculate incidence rates, and Cox proportional hazards models were used to examine the association between exposures and outcomes while adjusting for seizure risk factors. RESULTS: Among 1 782 402 beneficiaries, we identified 10 393 (0.6%) beneficiaries with cirrhosis and 19 557 (1.1%) with mild, noncirrhotic liver disease. Individuals with liver disease were older and had more seizure risk factors than those without liver disease. Over 4.6 ± 2.2 years of follow-up, 49 843 (2.8%) individuals were diagnosed with seizures and 25 patients (0.001%) were diagnosed with status epilepticus. Cirrhosis was not associated with seizures (hazard ratio [HR] = 1.1, 95% confidence interval [CI] = 1.0-1.3), but there was an association with status epilepticus (HR = 1.9, 95% CI = 1.3-2.8). Mild liver disease was not associated with a higher risk of seizures (HR = 0.8, 95% CI = 0.6-0.9) or status epilepticus (HR = 1.1, 95% CI = 0.7-1.5). SIGNIFICANCE: In a large, population-based cohort, we found an association between cirrhosis and status epilepticus, but no overall association between liver disease and seizures.

Adjunctive steroid therapy versus antibiotics alone for acute endophthalmitis after intraocular procedure.

BACKGROUND: Endophthalmitis refers to severe infection within the eye that involves the aqueous humor or vitreous humor, or both, and threatens vision. Most cases of endophthalmitis are exogenous (i.e. due to inoculation of organisms from an outside source), and most exogenous endophthalmitis is acute and occurs after an intraocular procedure. The mainstay of treatment is emergent administration of broad-spectrum intravitreous antibiotics. Due to their anti-inflammatory effects, steroids in conjunction with antibiotics have been proposed to be beneficial in endophthalmitis management. OBJECTIVES: To assess the effects of antibiotics combined with steroids versus antibiotics alone for the treatment of acute endophthalmitis following intraocular surgery or intravitreous injection. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 11), MEDLINE Ovid (1946 to 8 December 2016), Embase Ovid (1980 to 8 December 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 8 December 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 8 December 2016, ClinicalTrials.gov (www.clinicaltrials.gov); searched 8 December 2016, and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 8 December 2016. We did not use any date or language restrictions in the electronic searches for trials. SELECTION CRITERIA: We included randomized controlled trials comparing the effectiveness of adjunctive steroids with antibiotics alone in the management of acute, clinically diagnosed endophthalmitis following intraocular surgery or intravitreous injection. We excluded trials with participants with endogenous endophthalmitis unless outcomes were reported by source of infection. We imposed no restrictions on the method or order of administration, dose, frequency, or duration of antibiotics and steroids. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, assessed risk of bias, and extracted data using methods expected by Cochrane. We contacted study authors to try to obtain missing information or information to clarify risk of bias. We conducted a meta-analysis for any outcomes that were reported by at least two studies. Outcomes reported from single studies were summarized in the text. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included three trials with a total of 95 randomized participants in this review and identified one ongoing trial. The studies were conducted in South Africa, India, and the Netherlands. Out of the 92 analyzed participants, 91 participants were diagnosed with endophthalmitis following cataract surgery. In the remaining participant, endophthalmitis was attributable to penetrating keratoplasty. All studies used intravitreous dexamethasone for adjunctive steroid therapy and a combination of two intravitreous antibiotics that provided gram-positive and gram-negative coverage for the antibiotic therapy. We judged one trial to be at overall low risk of bias and two studies to be at overall unclear risk of bias due to lack of reporting of study methods. None of the three trials had been registered in a clinical trial register.While none of the included studies reported the primary outcome of complete resolution of endophthalmitis as defined in our protocol, one study reported combined anatomical and functional success (i.e. proportion of participants with intraocular pressure of at least 5 mmHg and visual acuity of at least 6/120). Very low-certainty evidence suggested no difference in combined success when comparing adjunctive steroid antibiotics alone (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.80 to 1.45; 32 participants). Low-certainty evidence from two studies showed that a higher proportion of participants who received adjunctive dexamethasone had a good visual outcome (Snellen visual acuity 6/6 to 6/18) at three months compared with those in the antibiotics-alone group (RR 1.95, 95% CI 1.05 to 3.60; 60 participants). Similarly, low-certainty evidence from one study suggested that more participants in the dexamethasone group had a good visual outcome at 12 months compared to those who did not receive dexamethasone (RR 2.00, 95% CI 0.98 to 4.08; 28 participants). Investigators of one study reported improvement in visual acuity, but we could not estimate the effect of adjunctive steroid therapy because the study investigators did not provide standard deviations or standard errors. Two studies reported adverse events (retinal detachment, hypotony, proliferative vitreoretinopathy, and seclusion of pupil). The total numbers of adverse events were 8 out of 30 (26.7%) for those who received dexamethasone versus 6 out of 30 (20.0%) for those who did not. We could only perform a pooled analysis for the occurrence of retinal detachment; any difference between the two treatment groups was uncertain (RR 1.57, 95% CI 0.50 to 4.90; 60 participants) (very low-certainty evidence). No study reported intraocular pressure or cost outcomes. AUTHORS' CONCLUSIONS: Current evidence on the effectiveness of adjunctive steroid therapy versus antibiotics alone in the management of acute endophthalmitis after intraocular surgery is inadequate. We found no studies that had enrolled cases of acute endophthalmitis following intravitreous injection. A combined analysis of two studies suggests adjunctive steroids may provide a higher probability of having a good visual outcome at three months than not using adjunctive steroids. However, considering that most of the confidence intervals crossed the null and that this review was limited in scope and applicability to clinical practice, it is not possible to conclude whether the use adjunctive steroids is effective at this time. Any future trials should examine whether adjunctive steroids may be useful in certain clinical settings such as type of causative organism or etiology. These studies should include outcomes that take patient's symptoms and clinical examination into account, report outcomes in a uniform and consistent manner, and follow up at short- and long-term intervals.

Simultaneous knock-down of Bcl-xL and Mcl-1 induces apoptosis through Bax activation in pancreatic cancer cells.

Anti-apoptotic Bcl-2 family proteins have been reported to play an important role in apoptotic cell death of human malignancies. The aim of this study was to delineate the mechanism of anti-apoptotic Bcl-2 family proteins in pancreatic cancer (PaCa) cell survival. We first analyzed the endogenous expression and subcellular localization of anti-apoptotic Bcl-2 family proteins in six PaCa cell lines by Western blot. To delineate the functional role of Bcl-2 family proteins, siRNA-mediated knock-down of protein expression was used. Apoptosis was measured by Cell Death ELISA and Hoechst 33258 staining. In the results, the expression of anti-apoptotic Bcl-2 family proteins varied between PaCa cell lines. Mcl-1 knock-down resulted in marked cleavage of PARP and induction of apoptosis. Down-regulation of Bcl-2 or Bcl-xL had a much weaker effect. Simultaneous knock-down of Bcl-xL and Mcl-1 strongly induced apoptosis, but simultaneous knock-down of Bcl-xL/Bcl-2 or Mcl-1/Bcl-2 had no additive effect. The apoptosis-inducing effect of simultaneous knock-down of Bcl-xL and Mcl-1 was associated with translocation of Bax from the cytosol to the mitochondrial membrane, cytochrome c release, and caspase activation. These results demonstrated that Bcl-xL and Mcl-1 play an important role in pancreatic cancer cell survival. Targeting both Bcl-xL and Mcl-1 may be an intriguing therapeutic strategy in PaCa.

RET Inhibitors in RET Fusion-Positive Lung Cancers: Past, Present, and Future.

While activating RET fusions are identified in various cancers, lung cancer represents the most common RET fusion-positive tumor. The clinical drug development of RET inhibitors in RET fusion-positive lung cancers naturally began after RET fusions were first identified in patient tumor samples in 2011, and thereafter paralleled drug development in RET fusion-positive thyroid cancers. Multikinase inhibitors were initially tested with limited efficacy and substantial toxicity. RET inhibitors were then designed with improved selectivity, central nervous system penetrance, and activity against RET fusions and most RET mutations, including resistance mutations. Owing their success to these rationally designed features, the first-generation selective RET tyrosine kinase inhibitors (TKIs) had higher response rates, more durable disease control, and an improved safety profile compared to the multikinase inhibitors. This led to lung and thyroid cancer, and later tumor-agnostic regulatory approvals. While next-generation RET TKIs were designed to abrogate uncommon on-target (e.g., solvent front mutation) resistance to selpercatinib and pralsetinib, many of these drugs lacked the selectivity of the first-generation TKIs, raising the question of what the future holds for drug development in RET-dependent cancers.