The Utility of Echocardiogram in the Workup of Ischemic Stroke Patients.

BACKGROUND: Cardiac sources of emboli can be identified by transthoracic echocardiogram (TTE). The Canadian Best Practice Guidelines recommend routine use of TTE in the initial workup of ischemic stroke when an embolic source is suspected. However, TTEs are commonly ordered for all patients despite insufficient evidence to justify cost-effectiveness. We aim to evaluate the TTE ordering pattern in the initial workup of ischemic stroke at a regional Stroke Center in Central South Ontario and determine the proportion of studies which led to a change in management and affected length of stay (LOS). METHODS: Hospital records of 520 patients with a discharge diagnosis of TIA or ischemic stroke between October 2016 and June 2017 were reviewed to gather information. RESULTS: 477 patients admitted for TIA or ischemic stroke met inclusion criteria. 67.9% received TTE, out of which 6.0% had findings of cardiac sources of emboli including left ventricular thrombus, atrial septal aneurysm, PFO, atrial myxoma, and valvular vegetation. 2.5% of all TTE findings led to change in medical management. The median LOS of patients who underwent TTE was 2 days longer (p < 0.00001). CONCLUSION: TTE in the initial workup of TIA or ischemic stroke remains common practice. The yield of TTEs is low, and the proportion of studies that lead to changes in medical management is minimal. TTE completion was associated with increased LOS and may result in increased healthcare spending; however, additional factors prolonging the LOS could not be excluded.

Inpatient vs outpatient management of pregnancies with vasa previa: A historical cohort study.

INTRODUCTION: Vasa previa, a condition where unprotected fetal blood vessels lie in proximity to the internal cervical opening, is a potentially lethal obstetric complication. The precarious situation of these vessels increases the risk of fetal hemorrhage with spontaneous or artificial rupture of membranes, frequently causing fetal/neonatal demise or severe morbidity. As a result, in many centers, inpatient management forms the mainstay when vasa previa is diagnosed antenatally. This study aimed to determine whether a subpopulation of pregnancies diagnosed antenatally with vasa previa could be safely managed as outpatients. MATERIAL AND METHODS: We reviewed all cases of vasa previa in singleton pregnancies, with no fetal anomalies, diagnosed at Mount Sinai Hospital, Toronto, from January 2008 to December 2017. Cases were categorized into three arms for analysis: outpatients (OP), asymptomatic hospitalized (ASH) and symptomatic hospitalized (SH). The SH arm included patients admitted with any antepartum bleeding or suspicious fetal non-stress test. Those that presented with symptomatic uterine activity/threatened preterm labor and delivered within 7 days of diagnosis were excluded from the study. Records were analyzed for details on hospitalization, antenatal corticosteroid administration, cervical length measurements, and fetal/neonatal mortality and morbidity. RESULTS: Of the 84 antenatally-diagnosed cases of vasa previa, 47 fulfilled eligibility criteria. A total of 15 cases were managed as OP, 22 as ASH and 10 as SH. Unplanned cesareans were highest in the SH arm (40% vs. 0% ASH vs. 13.3% OP). Those in the SH arm delivered earliest (median 33.8 weeks, interquartile range (IQR) 33.2-34.3 weeks). Of the asymptomatic patients, those in the ASH arm delivered earlier than those in the OP arm (35.3 [34.6-36.2] weeks vs. 36.7 [35.6-37.2] weeks, p = 0.037). There were no cases of fetal/neonatal death, anemia or severe neonatal morbidity and no significant differences between groups based on cervical length or antenatal corticosteroid administration. CONCLUSIONS: Our study suggests that asymptomatic women with an antenatal diagnosis of vasa previa, singleton pregnancies, and at low risk for preterm birth may safely managed as outpatients, as long as they are able to access hospital promptly in the event of antepartum bleeding or early labor.

Biopsy-proven PML in an HIV-negative patient with discoid lupus: Failure to detect JC virus in CSF.

We present a case of a 58-year-old man with a history of severe discoid lupus erythematosus and acute encephalopathy and incoordination. Antinuclear antibody testing was weakly positive but all other laboratory tests for systemic lupus erythematosus were negative and serum quantitative immunoglobulins and lymphocytes were normal. MRI brain showed T2/FLAIR hyperintensities within the bilateral parietal and temporal lobes with involvement of subcortical U fibers. CSF PCR was negative for varicella-zoster virus, herpes simplex, JCV and BK virus. However, JCV antibody index was elevated (3.88; reference: < 0.2). Right parietal brain biopsy was consistent with JCV infection and diagnostic of progressive multifocal leukoencephalopathy (PML). To the best of our knowledge, this is the first reported case of PML in a patient with discoid lupus without other traditional risk factors for the disease and highlights the need for clinical vigilance in this patient population.

Arachnoiditis, a complication of epidural blood patch for the treatment of low-pressure headache: A case report and systematic review.

OBJECTIVE: To report a case of arachnoiditis as a complication of epidural blood patch procedures and to systematically review the diagnostic workup, clinical outcomes, and treatment modalities reported in the literature. BACKGROUND: Epidural blood patching is an effective treatment for low-pressure headache secondary to spontaneous cerebrospinal fluid leak or iatrogenic post-dural puncture. Spontaneous intracranial hypotension is believed to be a rare headache disorder, but recently has been diagnosed at higher frequencies, making it an important differential diagnosis for intractable headaches. Arachnoiditis has surfaced as a rare complication of epidural blood patching. Symptom presentation does not always correlate with evidence of meningeal enhancement on imaging. Optimal methods for treatment remain largely unknown. METHODS: Databases Embase and PubMed were searched for all published studies on arachnoiditis post-epidural blood patch using a combination of the following medical subject headings and keywords: arachnoiditis, arachnoid inflammation, adverse event, and epidural blood patch. All original English-language articles that described arachnoid and/or meningeal inflammation in conjunction with epidural blood patch procedures were included for analysis. Title and abstract screening, data extraction, and risk of bias assessment were conducted independently and in duplicate by two reviewers. RESULTS: Seven other cases of arachnoiditis post-blood patch placement have been documented, most of which were diagnosed via magnetic resonance imaging. Six of these were a result of a spinal-epidural anesthesia for labor and delivery. Common symptoms reported were headache, back and radicular pain, paresthesia, and motor weakness. There are currently no proven consensus-based treatment recommendations available. While intravenous methylprednisolone followed by oral prednisone taper was found to be effective in the case presented, the benefit of other multi-modal therapies was unclear. CONCLUSIONS: Headache specialists who treat postural headache should be aware of arachnoiditis as a potentially severe complication of epidural blood patch. The case presented is the first of its kind to report arachnoiditis as a complication of high-volume blood patch for the treatment of spontaneous intracranial hypotension. More studies are required to determine suitable treatment options for post-epidural blood patch arachnoiditis.

Variations in reported outcomes in studies on vasa previa: a systematic review.

OBJECTIVE: To evaluate reported outcomes of published studies on the diagnosis and management of vasa previa in pregnancy. MATERIALS AND METHODS: Databases such as MEDLINE, Embase, Cochrane, PubMed, and ClinicalTrials.gov were searched up to March 2018 for all published studies on vasa previa using combinations of the following medical subject headings and key words: vasa previa, placenta previa, low-lying placenta, succenturiate lobe or placenta, bilobed or bilobate placenta, and velamentous insertion. All original human research that described maternal, obstetric, placental, fetal or neonatal outcomes relating to pregnancies with vasa previa were included for analysis. Title and abstract screening and data extraction was conducted independently and in duplicate by 2 reviewers for all studies until total agreement for eligibility was achieved. Data extraction was also conducted in duplicate in approximately 50% of studies reviewed. RESULTS: A total of 160 published studies (1004 pregnancies) were included. There was a wide range of reported outcomes, many of which were sparingly reported. The most commonly reported maternal outcomes included mode of delivery, presence of antepartum hemorrhage, time of diagnosis, and rupture of membranes. The presence of known risk factors for vasa previa such as a low-lying placenta, succenturiate or bilobed placenta, and (velamentous) cord insertion was incorrectly reported as "outcomes" in many studies. The most commonly reported fetal/neonatal outcomes included fetal heart rate, gestational age at delivery, birthweight, Apgar score, presence of neonatal anemia, cord blood gas measurements, need for blood transfusion, and death. Of note, only 3 studies reported outcomes related to life impact, maternal social and emotional functioning, perceived delivery of care, or resource utilization. CONCLUSION: Despite the profound effect the diagnosis of vasa previa has on pregnant women, families, and healthcare systems, studies on vasa previa seldom report outcomes related to life impact and resource utilization. There is a need for the development of a core outcome set-a minimum standard set of outcomes deemed important by pregnant women and other stakeholders involved in their care-to standardize outcome reporting in future studies on vasa previa.

Vasa previa and associated risk factors: a systematic review and meta-analysis.

OBJECTIVE: To systematically review published literature and calculate the prevalence of vasa previa and its known risk factors. MATERIALS AND METHODS: MEDLINE, Embase, the Cochrane Library, PubMed (non-MEDLINE and in process), and www.clinicaltrials.gov were searched from inception to March 2018 using indexing terms "vasa previa," "placenta previa," "low lying placenta," "succenturiate lobe," "bilobate placenta," "bilobed placenta," and "velamentous insertion." All original research studies reporting on 5 or more pregnancies with vasa previa were included. The search was limited to studies on human data and those published in the English language. Two reviewers independently screened titles and abstracts, completed data extraction, and assessed reporting quality using the Study Quality Assessment Tool for Case Series Studies of the National Heart, Lung, and Blood Institute. Disagreements were discussed and resolved at each step of the process. RESULTS: We included 21 studies that reported 428 pregnancies with vasa previa of 1,027,918 deliveries (0.46 cases of vasa previa per 1000 deliveries). These studies fared well on risk of bias assessment using the Study Quality Assessment Tool for Case Series Studies of the National Heart, Lung, and Blood Institute. The prevalence and 95% confidence intervals of known risk factors for vasa previa included a low-lying placenta (61.5%, 53.0%-70.0%), velamentous cord insertion (52.2%, 39.6%-64.7%), bilobed or succenturiate lobed placenta (33.3%, 20.9%-45.7%), use of in vitro fertilization (26.4%, 16.0%-36.8%), and multiple gestation (8.92%, 5.33%-12.5%). CONCLUSION: Vasa previa affects 0.46 cases per 1000 pregnancies. Given the high prevalence of prenatally detectable risk factors in affected pregnancies, the cost-effectiveness of screening strategies for vasa previa either in isolation, using a risk factor-based approach, or universally, in tandem with cervical-length screening using transvaginal ultrasound, should be revisited.

Core outcome set for studies on pregnant women with vasa previa (COVasP): a study protocol.

INTRODUCTION: Vasa previa is a condition where fetal blood vessels run unprotected in the membranes, outside the umbilical cord, and cross the internal opening of the cervix. During rupture of membranes, these vessels can rupture and put the baby at serious risk of severe blood loss and death. Numerous studies are being conducted to improve diagnostic modalities and establish clear management plans to improve pregnancy outcomes. However, the lack of a standardised set of outcomes for studies on vasa previa makes it difficult to compare study findings and draw meaningful conclusions. Through this project, we will be developing a core outcome set for studies on pregnant women with vasa previa (COVasP). METHODS AND ANALYSIS: The development of COVasP will involve five steps. The first will be a systematic review, in which we will generate a long list of outcomes based on published studies in pregnancies complicated with vasa previa. The second will involve in-depth interviews with current and former patients, their family members and healthcare providers who care for these patients. This will be followed by a two-round Delphi survey, which will aim to narrow down the long list of outcomes into those considered important by four groups of 'stakeholders': (1) patients, family members and patient advocates/representatives, (2) healthcare providers, (3) researchers, epidemiologists and methodologists and (4) other stakeholders directly or indirectly involved in the management of these pregnancies such as administrators, guideline developers and policymakers. The fourth step will involve a face-to-face consensus meeting using a nominal group approach to establish a finalised core outcome set. The final step will involve measuring and defining the identified outcomes using a combination of systematic reviews and Delphi surveys. ETHICS AND DISSEMINATION: This study as well as consent forms for stakeholder participation have received approval from the Mount Sinai Hospital Research Ethics Board (REB number 18-0173-E) on 05 September 2018 and the Human Research Ethics Committee at The University of Technology Sydney, Australia on 30 July 2019 (UTS HREC reference number ETH19-3718). All progress will be documented on the international prospective register of systematic reviews and Core Outcome Measures in Effectiveness Trials databases. REGISTRATION DETAILS: http://www.comet-initiative.org/studies/details/1117.

Salicylate enhances the response of prostate cancer to radiotherapy.

BACKGROUND: Radiotherapy (RT) is a key therapeutic modality for prostate cancer (PrCa), but RT resistance necessitates dose-escalation, often causing bladder and rectal toxicity. Aspirin, a prodrug of salicylate (SAL), has been associated with improved RT response in clinical PrCa cases, but the potential mechanism mediating this effect is unknown. SAL activates the metabolic stress sensor AMP-activated protein kinase (AMPK), which inhibits de novo lipogenesis, and protein synthesis via inhibition of Acetyl-CoA Carboxylase (ACC), and the mammalian Target of Rapamycin (mTOR), respectively. RT also activates AMPK through a mechanism distinctly different from SAL. Therefore, combining these two therapies may have synergistic effects on suppressing PrCa. Here, we examined the potential of SAL to enhance the response of human PrCa cells and tumors to RT. METHODS: Androgen-insensitive (PC3) and -sensitive (LNCaP) PrCa cells were subjected to proliferation and clonogenic survival assays after treatment with clinically relevant doses of SAL and RT. Balb/c nude mice with PC3 xenografts were fed standard chow diet or chow diet supplemented with 2.5 g/kg salsalate (SAL pro-drug dimer) one week prior to a single dose of 0 or 10 Gy RT. Immunoblotting analysis of signaling events in the DNA repair and AMPK-mTOR pathways and lipogenesis were assessed in cells treated with SAL and RT. RESULTS: SAL inhibited proliferation and clonogenic survival in PrCa cells and enhanced the inhibition mediated by RT. Salsalate, added to diet, enhanced the anti-tumor effects of RT in PC3 tumor xenografts. RT activated genotoxic stress markers and the activity of mTOR pathway and AMPK and mediated inhibitory phosphorylation of ACC. Interestingly, SAL enhanced the effects of RT on AMPK and ACC but blocked markers of mTOR activation. CONCLUSIONS: Our results show that SAL can enhance RT responses in PrCa. Salsalate is a promising agent to investigate this concept in prospective clinical trials of PrCa in combination with RT.

Oligomerization of equilibrative nucleoside transporters: a novel regulatory and functional mechanism involving PKC and PP1.

Equilibrative nucleoside transporters (ENTs) translocate nucleosides and nucleobases across plasma membranes, as well as a variety of anti-cancer, -viral, and -parasite nucleoside analogs. They are also key members of the purinome complex and regulate the protective and anti-inflammatory effects of adenosine. Despite their important role, little is known about the mechanisms involved in their regulation. We conducted membrane yeast 2-hybrid and coimmunoprecipitation studies and identified, for the first time to our knowledge, the existence of protein-protein interactions between human ENT1 and ENT2 (hENT1 and hENT2) proteins in human cells and the formation of hetero- and homo-oligomers at the plasma membrane and the submembrane region. The use of NanoLuc Binary Technology allowed us to analyze changes in the oligomeric status of hENT1 and hENT2 and how they rapidly modify the uptake profile for nucleosides and nucleobases and allow cells to respond promptly to external signals or changes in the extracellular environment. These changes in hENTs oligomerization are triggered by PKC activation and subsequent action of protein phosphatase 1.-Grañe-Boladeras, N., Williams, D., Tarmakova, Z., Stevanovic, K., Villani, L. A., Mehrabi, P., Siu, K. W. M., Pastor-Anglada, M., Coe, I. R. Oligomerization of equilibrative nucleoside transporters: a novel regulatory and functional mechanism involving PKC and PP1.

Targeting metabolism and AMP-activated kinase with metformin to sensitize non-small cell lung cancer (NSCLC) to cytotoxic therapy: translational biology and rationale for current clinical trials.

Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio-sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress. Metformin, a well-tolerated anti-diabetic agent, which blocks mitochondria oxidative phosphorylation complex I, became the poster child agent to elicit AMPK activity and tumor suppression. Metformin sensitizes NSCLC models to chemotherapy and radiation. Here, we discuss the rationale for targeting metabolism, the evidence supporting metformin as an anti-tumor agent and adjunct to cytotoxic therapy in NSCLC and we review retrospective evidence and on-going clinical trials addressing this concept.

The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration.

OBJECTIVE: The sodium-glucose transporter 2 (SGLT2) inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate that SGLT2 inhibitors may inhibit the growth of some cancer cells but the mechanism(s) remain unclear. METHODS: Cellular proliferation and clonogenic survival were used to assess the sensitivity of prostate and lung cancer cell growth to the SGLT2 inhibitors. Oxygen consumption, extracellular acidification rate, cellular ATP, glucose uptake, lipogenesis, and phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase, and the p70S6 kinase were assessed. Overexpression of a protein that maintains complex-I supported mitochondrial respiration (NDI1) was used to establish the importance of this pathway for mediating the anti-proliferative effects of Canagliflozin. RESULTS: Clinically achievable concentrations of Canagliflozin, but not Dapagliflozin, inhibit cellular proliferation and clonogenic survival of prostate and lung cancer cells alone and in combination with ionizing radiation and the chemotherapy Docetaxel. Canagliflozin reduced glucose uptake, mitochondrial complex-I supported respiration, ATP, and lipogenesis while increasing the activating phosphorylation of AMPK. The overexpression of NDI1 blocked the anti-proliferative effects of Canagliflozin indicating reductions in mitochondrial respiration are critical for anti-proliferative actions. CONCLUSION: These data indicate that like the biguanide metformin, Canagliflozin not only lowers blood glucose but also inhibits complex-I supported respiration and cellular proliferation in prostate and lung cancer cells. These observations support the initiation of studies evaluating the clinical efficacy of Canagliflozin on limiting tumorigenesis in pre-clinical animal models as well epidemiological studies on cancer incidence relative to other glucose lowering therapies in clinical populations.

Salicylate activates AMPK and synergizes with metformin to reduce the survival of prostate and lung cancer cells ex vivo through inhibition of de novo lipogenesis.

Aspirin, the pro-drug of salicylate, is associated with reduced incidence of death from cancers of the colon, lung and prostate and is commonly prescribed in combination with metformin in individuals with type 2 diabetes. Salicylate activates the AMP-activated protein kinase (AMPK) by binding at the A-769662 drug binding site on the AMPK ß1-subunit, a mechanism that is distinct from metformin which disrupts the adenylate charge of the cell. A hallmark of many cancers is high rates of fatty acid synthesis and AMPK inhibits this pathway through phosphorylation of acetyl-CoA carboxylase (ACC). It is currently unknown whether targeting the AMPK-ACC-lipogenic pathway using salicylate and/or metformin may be effective for inhibiting cancer cell survival. Salicylate suppresses clonogenic survival of prostate and lung cancer cells at therapeutic concentrations achievable following the ingestion of aspirin (<1.0 mM); effects not observed in prostate (PNT1A) and lung (MRC-5) epithelial cell lines. Salicylate concentrations of 1 mM increased the phosphorylation of ACC and suppressed de novo lipogenesis and these effects were enhanced with the addition of clinical concentrations of metformin (100 µM) and eliminated in mouse embryonic fibroblasts (MEFs) deficient in AMPK ß1. Supplementation of media with fatty acids and/or cholesterol reverses the suppressive effects of salicylate and metformin on cell survival indicating the inhibition of de novo lipogenesis is probably important. Pre-clinical studies evaluating the use of salicylate based drugs alone and in combination with metformin to inhibit de novo lipogenesis and the survival of prostate and lung cancers are warranted.