Publications by authors named "John Sinclair"

176 Publications

Bromodomain proteins regulate human cytomegalovirus latency and reactivation allowing epigenetic therapeutic intervention.

Proc Natl Acad Sci U S A 2021 Mar;118(9)

Cambridge Institute of Therapeutic Immunology and Infectious Disease, Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, United Kingdom;

Reactivation of human cytomegalovirus (HCMV) from latency is a major health consideration for recipients of stem-cell and solid organ transplantations. With over 200,000 transplants taking place globally per annum, virus reactivation can occur in more than 50% of cases leading to loss of grafts as well as serious morbidity and even mortality. Here, we present the most extensive screening to date of epigenetic inhibitors on HCMV latently infected cells and find that histone deacetylase inhibitors (HDACis) and bromodomain inhibitors are broadly effective at inducing virus immediate early gene expression. However, while HDACis, such as myeloid-selective CHR-4487, lead to production of infectious virions, inhibitors of bromodomain (BRD) and extraterminal proteins (I-BETs), including GSK726, restrict full reactivation. Mechanistically, we show that BET proteins (BRDs) are pivotally connected to regulation of HCMV latency and reactivation. Through BRD4 interaction, the transcriptional activator complex P-TEFb (CDK9/CycT1) is sequestered by repressive complexes during HCMV latency. Consequently, I-BETs allow release of P-TEFb and subsequent recruitment to promoters via the superelongation complex (SEC), inducing transcription of HCMV lytic genes encoding immunogenic antigens from otherwise latently infected cells. Surprisingly, this occurs without inducing many viral immunoevasins and, importantly, while also restricting viral DNA replication and full HCMV reactivation. Therefore, this pattern of HCMV transcriptional dysregulation allows effective cytotoxic immune targeting and killing of latently infected cells, thus reducing the latent virus genome load. This approach could be safely used to pre-emptively purge the virus latent reservoir prior to transplantation, thereby reducing HCMV reactivation-related morbidity and mortality.
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http://dx.doi.org/10.1073/pnas.2023025118DOI Listing
March 2021

CSF Rhinorrhea: A Rare Clinical Presentation of Choroid Plexus Papilloma.

Curr Oncol 2021 Jan 31;28(1):750-756. Epub 2021 Jan 31.

Radiation Oncology Division, The Ottawa Hospital-University of Ottawa, Ottawa, ON K1H 8L6, Canada.

Choroid plexus papilloma (CPP) is a rare brain tumour occurring mostly in infants and children. Most CPPs are intraventricular and present with symptoms and signs of increased intracranial pressure (ICP). This case report describes a middle-aged female who presented with spontaneous cerebrospinal fluid (CSF) rhinorrhea from a tumour located in the cerebellopontine angle (CPA). She underwent craniotomy with subtotal tumour resection and remained progression and rhinorrhea-free for several years. Upon clinical progression, the patient was treated with Cyberknife stereotactic radiosurgery. The patient clinically improved and demonstrated a favourable radiologic response to radiosurgery.
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http://dx.doi.org/10.3390/curroncol28010073DOI Listing
January 2021

Surgical or endovascular management of middle cerebral artery aneurysms: A randomized comparison.

World Neurosurg 2021 Feb 5. Epub 2021 Feb 5.

Centre Hospitalier de l'Université de Montréal (CHUM), Department of Radiology, Service of Neuroradiology, Montreal, Quebec, CANADA; Centre Hospitalier de l'Université de Montréal (CHUM), Research Centre, Interventional Neuroradiology Laboratory, Montréal, Quebec, CANADA. Electronic address:

Objective: There is little randomized data comparing clipping and coiling for middle cerebral artery (MCA) aneurysms. We analyzed results from MCA aneurysm patients enrolled in the CURES and ISAT-2 randomized trials.

Methods: Both trials are investigator-led parallel-group 1:1 randomized studies. CURES includes patients with 3-25 mm UIAs, and ISAT-2 includes RA patients for whom uncertainty remains after ISAT. The primary outcome measure of CURES is Treatment Failure: i) Failure to treat the aneurysm, ii) Intracranial hemorrhage during follow-up, or iii) Residual aneurysm at 1 year. The primary outcome of ISAT-2 is death or dependency (mRS>2) at 1 year. One year angiographic outcomes are systematically recorded.

Results: There were 100 unruptured and 71 ruptured MCA aneurysms. In CURES, 90 UIA patients have been treated, 10 await treatment. Surgical and endovascular management of unruptured MCA aneurysms led to Treatment Failure in 3/42 (7%;95%CI:0.02-0.19) for clipping and 13/48 (27%;95%CI:0.17-0.41) for coiling (P=0.025). All 71 RA patients have been treated. In ISAT-2, ruptured MCA aneurysm patients managed surgically were dead or dependent (mRS>2) in 7/38 (18%;95%CI:0.09-0.33) cases, and 8/33 (24%;95%CI:0.13-0.41) for endovascular. One year imaging results were available in 80 UIA and 62 RA patients. Complete aneurysm occlusion was found in 30/40 (75%;95%CI:0.60-0.86) UIA patients allocated clipping, and 14/40 (35%;95%CI:0.22-0.50) UIA patients allocated coiling. Complete aneurysm occlusion was found in 24/34 (71%;95%CI:0.54-0.83) RA patients allocated clipping, and 15/28 (54%;95%CI:0.36-0.70) RA patients allocated coiling.

Conclusions: Randomized data from two trials shows that better efficacy may be obtained with surgical management of MCA aneurysm patients.

Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifiers: NCT01139892, NCT01668563.
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http://dx.doi.org/10.1016/j.wneu.2021.01.142DOI Listing
February 2021

Using Primary Human Cells to Analyze Human Cytomegalovirus Biology.

Methods Mol Biol 2021 ;2244:51-81

Department of Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, UK.

The extensive tropism of human cytomegalovirus (HCMV) results in the productive infection of multiple cell types within the human host. However, infection of other cell types, such as undifferentiated cells of the myeloid lineage, give rise to nonpermissive infections. This aspect has been used experimentally to model latent infection, which is known to be established in the pluripotent CD34+ hematopoietic progenitor cell population resident in the bone marrow in vivo. The absence of a tractable animal model for studies of HCMV has resulted in a number of laboratories employing experimental infection of cells in vitro to simulate both HCMV lytic and latent infection. Herein, we will focus on the techniques used in our laboratory for the isolation and use of primary cells to study aspects of HCMV latency, reactivation, and lytic infection.
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http://dx.doi.org/10.1007/978-1-0716-1111-1_4DOI Listing
January 2021

Surgery and dose-escalated radiotherapy for a intracranial squamous cell carcinoma of the cerebellopontine angle.

Clin Transl Radiat Oncol 2021 Mar 27;27:99-102. Epub 2021 Jan 27.

Radiation Oncology Division, The Ottawa Hospital - University of Ottawa, Ottawa, ON, Canada.

We report an extremely rare case of intracranial squamous cell carcinoma of the cerebellopontine angle. The patient underwent craniotomy for debulking of the lesion to relieve mass effect on the brainstem and to establish a tissue diagnosis. Cancer staging revealed no other primary cancers and no evidence of metastatic disease. Postoperatively, he received image-guided intensity-modulated radiotherapy to the tumor bed followed by fractionated radiosurgery boost to the gross residual disease for a total average dose of 7000 cGy. He had a complete response to radiation and remains 42-months' disease-free post-treatment.
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http://dx.doi.org/10.1016/j.ctro.2021.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851331PMC
March 2021

Bromodomain Inhibitors as Therapeutics for Herpesvirus-Related Disease: All BETs Are Off?

Front Cell Infect Microbiol 2020 2;10:329. Epub 2020 Jul 2.

Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.

Although the ubiquitous human herpesviruses (HHVs) are rarely associated with serious disease of the healthy host, primary infection and reactivation in immunocompromised individuals can lead to significant morbidity and, in some cases, mortality. Effective drugs are available for clinical treatment, however resistance is on the rise such that new anti-viral targets, as well as novel clinical treatment strategies, are required. A promising area of development and pre-clinical research is that of inhibitors of epigenetic modifying proteins that control both cellular functions and the viral life cycle. Here, we briefly outline the interaction of the host bromo- and extra-terminal domain (BET) proteins during different stages of the HHVs' life cycles while giving a full overview of the published work using BET bromodomain inhibitors (BRDis) during HHV infections. Furthermore, we provide evidence that small molecule inhibitors targeting the host BET proteins, and BRD4 in particular, have the potential for therapeutic intervention of HHV-associated disease.
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http://dx.doi.org/10.3389/fcimb.2020.00329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343845PMC
July 2020

Understanding HCMV Latency Using Unbiased Proteomic Analyses.

Pathogens 2020 Jul 20;9(7). Epub 2020 Jul 20.

Department of Medicine, University of Cambridge, box 157, Level 5 Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.

Human cytomegalovirus (HCMV) establishes either a latent (non-productive) or lytic (productive) infection depending upon cell type, cytokine milieu and the differentiation status of the infected cell. Undifferentiated cells, such as precursor cells of the myeloid lineage, support a latent infection whereas terminally differentiated cells, such as monocytes or dendritic cells are an environment conducive to reactivation and support a lytic infection. The mechanisms which regulate HCMV in either a latent or lytic infection have been the focus of intense investigation with a view to developing novel treatments for HCMV-associated disease which can have a heavy clinical burden after reactivation or primary infection in, especially, the immune compromised. To this end, a number of studies have been carried out in an unbiased manner to address global changes occurring within the latently infected cell to address the molecular changes associated with HCMV latency. In this review, we will concentrate on the proteomic analyses which have been carried out in undifferentiated myeloid cells which either stably express specific viral latency associated genes in isolation or on cells which have been latently infected with virus.
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http://dx.doi.org/10.3390/pathogens9070590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399836PMC
July 2020

Unresectable Foramen Magnum Meningioma Treated With CyberKnife Robotic Stereotactic Radiosurgery.

Cureus 2020 Jun 2;12(6):e8409. Epub 2020 Jun 2.

Radiation Oncology, The Ottawa Hospital, Ottawa, CAN.

Meningiomas are tumors that originate from the meningeal or dural cover of the brain and are the most common primary benign brain tumors. Currently, the accepted management of these tumors is attempted total surgical excision when technically possible and associated with an acceptable risk. However, radiation therapy has been shown to provide excellent local control when used either as an adjunct to surgery or as a primary treatment. We present a case report of a 46-year-old female patient with an unresectable left foramen magnum meningioma resulting in headaches, neck pain, and swallowing difficulty. The patient underwent CyberKnife (Accuray Incorporated, Sunnyvale, CA) radiosurgery to a dose of 3,000 cGy in five fractions in March 2011. The patient tolerated treatment without complications and has remained clinically well with no ongoing cranial nerve deficits as of the last examination in late 2019. This demonstrates the excellent local control obtained when using radiosurgery as both a surgical adjunct and a primary treatment for meningiomas.
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http://dx.doi.org/10.7759/cureus.8409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331916PMC
June 2020

Intravitreal enzyme replacement preserves retinal structure and function in canine CLN2 neuronal ceroid lipofuscinosis.

Exp Eye Res 2020 08 1;197:108130. Epub 2020 Jul 1.

Neurodegenerative Diseases Research Laboratory, University of Missouri School of Medicine, Columbia, USA. Electronic address:

CLN2 neuronal ceroid lipofuscinosis is a hereditary neurodegenerative disorder characterized by progressive vision loss, neurological decline, and seizures. CLN2 disease results from mutations in TPP1 that encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Children with CLN2 neuronal ceroid lipofuscinosis experience ocular disease, characterized by progressive retinal degeneration associated with impaired retinal function and gradual vision loss culminating in total blindness. A similar progressive loss of retinal function is also observed in a dog CLN2 model with a TPP1 null mutation. A study was conducted to evaluate the efficacy of periodic intravitreal injections of recombinant human (rh) TPP1 in inhibiting retinal degeneration and preserving retinal function in the canine model. TPP1 null dogs received periodic intravitreal injections of rhTPP1 in one eye and vehicle in the other eye beginning at approximately 12 weeks of age. Ophthalmic exams, in vivo ocular imaging, and electroretinography (ERG) were repeated regularly to monitor retinal structure and function. Retinal histology was evaluated in eyes collected from these dogs when they were euthanized at end-stage neurological disease (43-46 weeks of age). Intravitreal rhTPP1 dosing prevented disease-related declines in ERG amplitudes in the TPP1-treated eyes. At end-stage neurologic disease, TPP1-treated eyes retained normal morphology while the contralateral vehicle-treated eyes exhibited loss of inner retinal neurons and photoreceptor disorganization typical of CLN2 disease. The treatment also prevented the development of disease-related focal retinal detachments observed in the control eyes. Uveitis occurred secondary to the administration of the rhTPP1 but did not hinder the therapeutic benefits. These findings demonstrate that periodic intravitreal injection of rhTPP1 preserves retinal structure and function in canine CLN2 disease.
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http://dx.doi.org/10.1016/j.exer.2020.108130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484259PMC
August 2020

Human Cytomegalovirus Interleukin 10 Homologs: Facing the Immune System.

Front Cell Infect Microbiol 2020 9;10:245. Epub 2020 Jun 9.

Center for Natural and Humanities Sciences, Federal University of ABC (UFABC), São Bernardo do Campo, Brazil.

Human Cytomegalovirus (HCMV) can cause a variety of health disorders that can lead to death in immunocompromised individuals and neonates. The HCMV lifecycle comprises both a lytic (productive) and a latent (non-productive) phase. HCMV lytic infection occurs in a wide range of terminally differentiated cell types. HCMV latency has been less well-studied, but one characterized site of latency is in precursor cells of the myeloid lineage. All known viral genes are expressed during a lytic infection and a subset of these are also transcribed during latency. The UL111A gene which encodes the viral IL-10, a homolog of the human IL-10, is one of these genes. During infection, different transcript isoforms of UL111A are generated by alternative splicing. The most studied of the UL111A isoforms are cmvIL-10 (also termed the "A" transcript) and LAcmvIL-10 (also termed the "B" transcript), the latter being a well-characterized latency associated transcript. Both isoforms can downregulate MHC class II, however they differ in a number of other immunomodulatory properties, such as the ability to bind the IL10 receptor and induce signaling through STAT3. There are also a number of other isoforms which have been identified which are expressed by differential splicing during lytic infection termed C, D, E, F, and G, although these have been less extensively studied. HCMV uses the viral IL-10 proteins to manipulate the immune system during lytic and latent phases of infection. In this review, we will discuss the literature on the viral IL-10 transcripts identified to date, their encoded proteins and the structures of these proteins as well as the functional properties of all the different isoforms of viral IL-10.
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http://dx.doi.org/10.3389/fcimb.2020.00245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296156PMC
June 2020

MultiHance as a contrast alternative for Gadovist allergic patients.

Radiol Case Rep 2020 Jul 30;15(7):850-853. Epub 2020 Apr 30.

Division of Radiation Oncology, The Ottawa Hospital, University of Ottawa, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada.

The dramatic rise in the use of contrast agents for diagnostic imaging within the last decade has largely contributed to the effectiveness of MR imaging, however even with the use of prophylaxis, adverse reactions to contrast, including anaphylaxis, still occur. We describe the case of a 46-year-old female patient with a hemangiopericytoma requiring ongoing contrast MR surveillance, and a documented anaphylactic reaction to Gadovist (gadobutrol injection) despite premedication. Allergy testing was positive to intradermal undiluted Gadovist, confirming an IgE-mediated Gadovist allergy, with subsequent skin testing by prick and intradermal negative to undiluted MultiHance. She went on to receive MultiHance prior to her subsequent MRI scans without clinical reaction and without premedication, demonstrating that there may be superior alternatives to traditionally used gadolinium dyes in patients with moderate to severe reactions, and warrants further investigation into the anaphylactoid characteristics between the different gadolinium-based contrast agents.
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http://dx.doi.org/10.1016/j.radcr.2020.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200611PMC
July 2020

Human cytomegalovirus major immediate early transcripts arise predominantly from the canonical major immediate early promoter in reactivating progenitor-derived dendritic cells.

J Gen Virol 2020 06;101(6):635-644

Institute of Immunity & Transplantation, University College London, Royal Free Campus, London NW3 2PF, UK.

Human cytomegalovirus latency and reactivation is a major source of morbidity in immune-suppressed patient populations. Lifelong latent infections are established in CD34+progenitor cells in the bone marrow, which are hallmarked by a lack of major lytic gene expression, genome replication and virus production. A number of studies have shown that inhibition of the major immediate early promoter (MIEP) - the promoter that regulates immediate early (IE) gene expression - is important for the establishment of latency and that, by extension, reactivation requires reversal of this repression of the MIEP. The identification of novel promoters (termed ip1 and ip2) downstream of the MIEP that can drive IE gene expression has led to speculation over the precise role of the MIEP in reactivation. In this study we show that IE transcripts arise from both the MIEP and ip2 promoter in the THP1 cell macrophage cell line and also CD14+monocytes stimulated with phorbol ester. In contrast, we show that in generated dendritic cells or macrophages that support HCMV reactivation IE transcripts arise predominantly from the MIEP and not the intronic promoters. Furthermore, inhibition of histone modifying enzyme activity confirms the view that the MIEP is predominantly regulated by the activity of cellular chromatin. Finally, we observe that ip2-derived IE transcription is cycloheximide-sensitive in reactivating DCs, behaviour consistent with an early gene designation. Taken together, these data argue that MIEP activity is still important for HCMV reactivation but ip2 activity could play cell-type-specific roles in reactivation.
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http://dx.doi.org/10.1099/jgv.0.001419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414444PMC
June 2020

Delayed pseudoprogression of a vestibular schwannoma postradiosurgery.

Radiol Case Rep 2020 Jun 11;15(6):749-752. Epub 2020 Apr 11.

Department of Radiation Oncology, The Ottawa Hospital, University of Ottawa, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.

Radiosurgery (RS) can offer excellent local control in the management of both benign and malignant tumors measuring less than 3 cm in size. A known late complication of radiosurgery is radiation necrosis which generally occurs within 6-18 months following treatment and has an increased risk of occurrence with higher radiation doses. The lower dose used to treat vestibular schwannomas (VS) makes this complication less frequent. Tumors that do not respond to radiosurgery and continue to grow may require surgical intervention. We report a case of a young male who received radiosurgery (18 Gy in 3 fractions) in February 2016 for a recurrent VS following initial debulking surgery in 2008. Follow-up imaging revealed an interval decrease in size by May 2017; however, by April 2018, there was significant interval increase in the cisternal components of the tumor. By September 2018, the lesion had increased by >50% (to a size of 29 mm) compared to May 2017. The patient agreed to undergo repeat surgical debulking. Upon review of the preoperative MRI, the cisternal component of the tumor had substantially decreased in size. Although uncommon, this reflects delayed, pseudoprogression which, in our case, was self-limiting. This raises a question regarding when to proceed with surgical intervention of growing VS following radiosurgery given the potential for delayed resolution of radiation necrosis and demonstrates a gap in our current literature involving surgery of VS following radiosurgery.
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http://dx.doi.org/10.1016/j.radcr.2020.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154998PMC
June 2020

Case report: Cyberknife radiosurgery for the treatment of disabling pain caused by vertebral body hemangioma.

J Radiosurg SBRT 2020 ;6(4):317-319

Department of Radiation Oncology, The Ottawa Cancer Centre, Ottawa, ON, Canada.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065896PMC
January 2020

Advances in cytomegalovirus (CMV) biology and its relationship to health, diseases, and aging.

Geroscience 2020 04 11;42(2):495-504. Epub 2020 Mar 11.

Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.

Cytomegalovirus (CMV) is one of the largest and most ubiquitous latent persistent viruses. Most humans are infected with CMV early in life, and all immunocompetent humans spend several decades living with CMV. In the vast majority of the hosts, CMV does not cause manifest disease, and CMV therefore can be considered part of normal aging for 50-90% of the human population worldwide. Experimental, clinical, and epidemiological studies suggest that CMV carriage can have nuanced outcomes, including both potentially harmful and potentially beneficial impacts on the host. We here present a summary of the 7th International Workshop on CMV and Immunosenescence, covering various aspects of the interplay between CMV and its mammalian hosts in the context of virus spread, immune evasion, antiviral immunity, as well as the impact on health span and aging.
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http://dx.doi.org/10.1007/s11357-020-00170-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205956PMC
April 2020

Single cell analysis reveals human cytomegalovirus drives latently infected cells towards an anergic-like monocyte state.

Elife 2020 Jan 22;9. Epub 2020 Jan 22.

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

Human cytomegalovirus (HCMV) causes a lifelong infection through establishment of latency. Although reactivation from latency can cause life-threatening disease, our molecular understanding of HCMV latency is incomplete. Here we use single cell RNA-seq analysis to characterize latency in monocytes and hematopoietic stem and progenitor cells (HSPCs). In monocytes, we identify host cell surface markers that enable enrichment of latent cells harboring higher viral transcript levels, which can reactivate more efficiently, and are characterized by reduced intrinsic immune response that is important for viral gene expression. Significantly, in latent HSPCs, viral transcripts could be detected only in monocyte progenitors and were also associated with reduced immune-response. Overall, our work indicates that regardless of the developmental stage in which HCMV infects, HCMV drives hematopoietic cells towards a weaker immune-responsive monocyte state and that this anergic-like state is crucial for the virus ability to express its transcripts and to eventually reactivate.
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http://dx.doi.org/10.7554/eLife.52168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039680PMC
January 2020

Neurofilament light is a treatment-responsive biomarker in CLN2 disease.

Ann Clin Transl Neurol 2019 12 8;6(12):2437-2447. Epub 2019 Dec 8.

Research, BioMarin Pharmaceutical Inc., Novato, California, 94949.

Objective: Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare, progressive, fatal neurodegenerative pediatric disorder resulting from deficiencies of the lysosomal enzyme tripeptidyl peptidase 1 that are caused by mutations in TPP1. Identifying biomarkers of CLN2 disease progression will be important in assessing the efficacy of therapeutic interventions for this disorder. Neurofilament light is an intrinsic component of healthy neurons; elevated circulating extracellular neurofilament light is a biomarker of neuropathology in several adult-onset neurological diseases. Our objective was to assess whether circulating neurofilament light is a biomarker that is responsive to enzyme replacement therapy (ERT) in CLN2 disease.

Methods: Using an ultrasensitive immunoassay, we assessed plasma neurofilament light changes during disease progression in a canine model of CLN2 disease and in ERT clinical trial CLN2 disease patients.

Results: In tripeptidyl peptidase 1 (TPP1)-null dogs (N = 11), but not in control dogs [N = 6 (TPP1 ) and N = 27 (WT)], neurofilament light levels increased more than tenfold above initial low baseline levels during disease progression. Before treatment in 21 human subjects with CLN2 disease (age range: 1.72-6.85 years), neurofilament light levels were 48-fold higher (P < 0.001) than in 7 pediatric controls (age range: 8-11 years). Pretreatment neurofilament light did not significantly correlate with disease severity or age. In CLN2 disease subjects receiving ERT, neurofilament light levels decreased by 50% each year over more than 3 years of treatment.

Interpretation: Our data indicate that circulating neurofilament light is a treatment-responsive biomarker in CLN2 disease and could contribute to understanding of the pathophysiology of this devastating pediatric disorder.
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http://dx.doi.org/10.1002/acn3.50942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917340PMC
December 2019

Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency.

mBio 2019 12 3;10(6). Epub 2019 Dec 3.

Department of Medicine, University of Cambridge, Cambridge, United Kingdom

Human cytomegalovirus (HCMV) latency is an active process which remodels the latently infected cell to optimize latent carriage and reactivation. This is achieved, in part, through the expression of viral genes, including the G-protein-coupled receptor US28. Here, we use an unbiased proteomic screen to assess changes in host proteins induced by US28, revealing that interferon-inducible genes are downregulated by US28. We validate that major histocompatibility complex (MHC) class II and two pyrin and HIN domain (PYHIN) proteins, myeloid cell nuclear differentiation antigen (MNDA) and IFI16, are downregulated during experimental latency in primary human CD14 monocytes. We find that IFI16 is targeted rapidly during the establishment of latency in a US28-dependent manner but only in undifferentiated myeloid cells, a natural site of latent carriage. Finally, by overexpressing IFI16, we show that IFI16 can activate the viral major immediate early promoter and immediate early gene expression during latency via NF-κB, a function which explains why downregulation of IFI16 during latency is advantageous for the virus. Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus which infects 50 to 100% of humans worldwide. HCMV causes a lifelong subclinical infection in immunocompetent individuals but is a serious cause of mortality and morbidity in the immunocompromised and neonates. In particular, reactivation of HCMV in the transplant setting is a major cause of transplant failure and related disease. Therefore, a molecular understanding of HCMV latency and reactivation could provide insights into potential ways to target the latent viral reservoir in at-risk patient populations.
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http://dx.doi.org/10.1128/mBio.02574-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890990PMC
December 2019

A Cancer Care Ontario Organizational Guideline for the Delivery of Stereotactic Radiosurgery for Brain Metastasis in Ontario, Canada.

Pract Radiat Oncol 2020 Jul - Aug;10(4):243-254. Epub 2019 Nov 26.

Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.

Purpose: In Ontario, Canada, there is increasing demand for stereotactic radiosurgery (SRS) for brain metastases. Recommendations for safe SRS delivery are needed to ensure that patients receive an equitable level of care across the province. This guideline presents the minimal recommendations for the organization and delivery of SRS with respect to the multidisciplinary team, applicable technologies, imaging requirements, quality assurance program, and patient follow-up.

Methods And Materials: The recommendations are based on the consensus opinion of the Cancer Care Ontario SRS for Brain Metastasis Guideline Development Group and clinical evidence when available. Primary consideration was given to the perceived benefits for patients and the small likelihood of harm arising from recommendation implementation. With the exception of the magnetic resonance imaging (MRI) follow-up strategy, all evidence was considered indirect and was provided by the working group in conjunction with their collective expertise in the field of SRS.

Results: The application of SRS requires a multidisciplinary team consisting of a radiation oncologist, neurosurgeon, neuroradiologist, medical physicist, radiation therapist, and medical dosimitrist. Volumetric imaging scanning parameters must be set to ensure sufficient spatial resolution, geometric fidelity, and contrast signal for brain metastases to be adequately and reliably visualized, contoured, and planned. The MRI-to-treatment time interval should be as short as possible, ideally no more than 7 days and certainly no more than 14 days as a maximum. Quality assurance programs must ensure that the treatment unit is in compliance with the manufacturer and with national and international guidelines. Follow-up of patients undergoing SRS should consist of routine clinical visits with an MRI every 2 to 3 months for the first year; every 3 to 4 months for the second and third year; and thereafter as determined by the multidisciplinary case conference.

Conclusions: The recommendations enclosed provide a framework for the minimum requirements for a cancer center in Ontario, Canada, to offer SRS for brain metastases.
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http://dx.doi.org/10.1016/j.prro.2019.11.002DOI Listing
November 2019

An iPSC-Derived Myeloid Lineage Model of Herpes Virus Latency and Reactivation.

Front Microbiol 2019 9;10:2233. Epub 2019 Oct 9.

Department of Medicine, University of Cambridge, Cambridge, United Kingdom.

Herpesviruses undergo life-long latent infection which can be life-threatening in the immunocompromised. Models of latency and reactivation of human cytomegalovirus (HCMV) include primary myeloid cells, cells known to be important for HCMV latent carriage and reactivation . However, primary cells are limited in availability, and difficult to culture and to genetically modify; all of which have hampered our ability to fully understand virus/host interactions of this persistent human pathogen. We have now used iPSCs to develop a model cell system to study HCMV latency and reactivation in different cell types after their differentiation down the myeloid lineage. Our results show that iPSCs can effectively mimic HCMV latency/reactivation in primary myeloid cells, allowing molecular interrogations of the viral latent/lytic switch. This model may also be suitable for analysis of other viruses, such as HIV and Zika, which also infect cells of the myeloid lineage.
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http://dx.doi.org/10.3389/fmicb.2019.02233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795026PMC
October 2019

Human Cytomegalovirus Upregulates Expression of HCLS1 Resulting in Increased Cell Motility and Transendothelial Migration during Latency.

iScience 2019 Oct 14;20:60-72. Epub 2019 Sep 14.

Cambridge University, Department of Medicine, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. Electronic address:

Human cytomegalovirus establishes a lifelong, latent infection in the human host and can cause significant morbidity and mortality, particularly, in immunocompromised individuals. One established site of HCMV latency and reactivation is in cells of the myeloid lineage. In undifferentiated myeloid cells, such as CD14+ monocytes, virus is maintained latently. We have recently reported an analysis of the total proteome of latently infected CD14+ monocytes, which identified an increase in hematopoietic lineage cell-specific protein (HCLS1). Here we show that this latency-associated upregulation of HCLS1 occurs in a US28-dependent manner and stabilizes actin structure in latently infected cells. This results in their increased motility and ability to transit endothelial cell layers. Thus, latency-associated increases in monocyte motility could aid dissemination of the latently infected reservoir, and targeting this increased motility could have an impact on the ability of latently infected monocytes to distribute to tissue sites of reactivation.
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http://dx.doi.org/10.1016/j.isci.2019.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817630PMC
October 2019

Intraoperative Flash Visual Evoked Potential Recording and Relationship to Visual Outcome.

Can J Neurol Sci 2019 05 14;46(3):295-302. Epub 2019 Mar 14.

Department of Surgery, Division of Neurosurgery,The Ottawa Hospital,Ottawa, ON,Canada.

Objective: To determine the relationship between intraoperative flash visual evoked potential (FVEP) monitoring and visual function.

Methods: Intraoperative FVEPs were recorded from electrodes placed in the scalp overlying the visual cortex (Oz) after flashing red light stimulation delivered by Cadwell LED stimulating goggles in 89 patients. Restrictive filtering (typically 10-100 Hz), optimal reject window settings, mastoid reference site, total intravenous anesthetic (TIVA), and stable retinal stimulation (ensured by concomitant electroretinogram [ERG] recording) were used to enhance FVEP reproducibility.

Results: The relationship between FVEP amplitude change and visual outcome was determined from 179 eyes. One eye had a permanent intraoperative FVEP loss despite stable ERG, and this eye had new, severe postoperative visual dysfunction. Seven eyes had transient significant FVEP change (>50% amplitude decrease that recovered by the end of surgery), but only one of those had a decrease in postoperative visual acuity. FVEP changes in all eight eyes (one permanent FVEP loss plus seven transient FVEP changes) were related to surgical manipulation. In each case the surgeon was promptly informed of the FVEP deterioration and took remedial action. The other eyes did not have FVEP changes, and none of those eyes had new postoperative visual deficits.

Conclusions: Our FVEP findings relate to visual outcome with a sensitivity and specificity of 1.0. New methods for rapidly acquiring reproducible FVEP waveforms allowed for timely reporting of significant FVEP change resulting in prompt surgical action. This may have accounted for the low postoperative visual deficit rate (1%) in this series.
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http://dx.doi.org/10.1017/cjn.2019.4DOI Listing
May 2019

HCMV latency: what regulates the regulators?

Med Microbiol Immunol 2019 Aug 14;208(3-4):431-438. Epub 2019 Feb 14.

Department of Medicine, University of Cambridge, Box 157 Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.

Human cytomegalovirus (HCMV) latency and reactivation is regulated by the chromatin structure at the major immediate early promoter (MIEP) within myeloid cells. Both cellular and viral factors are known to control this promoter during latency, here we will review the known mechanisms for MIEP regulation during latency. We will then focus on the virally encoded G-protein coupled receptor, US28, which suppresses the MIEP in early myeloid lineage cells. The importance of this function is underlined by the fact that US28 is essential for HCMV latency in CD34 progenitor cells and CD14 monocytes. We will describe cellular signalling pathways modulated by US28 to direct MIEP suppression during latency and demonstrate how US28 is able to 'regulate the regulators' of HCMV latency. Finally, we will describe how cell-surface US28 can be a target for antiviral therapies directed at the latent viral reservoir.
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http://dx.doi.org/10.1007/s00430-019-00581-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647427PMC
August 2019

Monocytes Latently Infected with Human Cytomegalovirus Evade Neutrophil Killing.

iScience 2019 Feb 8;12:13-26. Epub 2019 Jan 8.

Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. Electronic address:

One site of latency of human cytomegalovirus (HCMV) in vivo is in undifferentiated cells of the myeloid lineage. Although latently infected cells are known to evade host T cell responses by suppression of T cell effector functions, it is not known if they must also evade surveillance by other host immune cells. Here we show that cells latently infected with HCMV can, indeed, be killed by host neutrophils but only in a serum-dependent manner. Specifically, antibodies to the viral latency-associated US28 protein mediate neutrophil killing of latently infected cells. To address this mechanistically, a full proteomic screen was carried out on latently infected monocytes. This showed that latent infection downregulates the neutrophil chemoattractants S100A8/A9, thus suppressing neutrophil recruitment to latently infected cells. The ability of latently infected cells to inhibit neutrophil recruitment represents an immune evasion strategy of this persistent human pathogen, helping to prevent clearance of the latent viral reservoir.
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http://dx.doi.org/10.1016/j.isci.2019.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352302PMC
February 2019

Prospective comparative diagnostic accuracy evaluation of dynamic contrast-enhanced (DCE) vs. dynamic susceptibility contrast (DSC) MR perfusion in differentiating tumor recurrence from radiation necrosis in treated high-grade gliomas.

J Magn Reson Imaging 2019 08 5;50(2):573-582. Epub 2019 Jan 5.

University of Ottawa, Ottawa, Ontario, Canada.

Background: The appearance of a new enhancing lesion after surgery and chemoradiation for high-grade glioma (HGG) presents a common diagnostic dilemma. Histopathological analysis remains the reference standard in this situation.

Purpose: To prospectively compare the diagnostic accuracy of dynamic contrast-enhanced (DCE) vs. dynamic susceptibility contrast (DSC) in differentiating tumor recurrence (TR) from radiation necrosis (RN).

Study Type: Prospective diagnostic accuracy study.

Population: In all, 98 consecutive treated HGG patients with new enhancing lesion. We excluded 32 patients due to inadequate follow-up or technical limitation.

Field Strength/sequence: 3 T DCE and DSC MR.

Assessment: Histogram and hot-spot analysis of cerebral blood volume (CBV), corrected CBV, K , area under the curve (AUC), and plasma volume (Vp). The reference standard of TR and/or RN was determined by histopathology in 43 surgically resected lesions or by clinical/imaging follow-up in the rest.

Statistical Tests: Mann-Whitney U-tests, receiver operating characteristic (ROC) curve, and logistic regression analysis.

Results: A total of 68 lesions were included. There were 37 TR, 28 RN, and three lesions with equal proportions of TR and RN. TR had significantly higher CBV, corrected CBV, CBV ratio, corrected CBV ratio, AUC ratio, and Vp ratio (P < 0.05) than RN on hot-spot analysis. CBV had the highest diagnostic accuracy (AUROC 0.71). On histogram analysis, TR had higher CBV and corrected CBV maximal value compared with RN (P = 0.006, AUROC = 0.70). Only CBV on hot-spot analysis remained significant after correction for multiple comparison, with no significant improvement in diagnostic accuracy when using a combination of parameters (AUROC 0.71 vs. 0.76, P = 0.24).

Data Conclusion: DSC-derived CBV is the most accurate perfusion parameter in differentiating TR and RN. DSC and DCE-derived parameters reflecting the blood volume in an enhancing lesion are more accurate than the DCE-derived parameter K . Clinical practice may be best guided by blood volume measurements, rather than permeability assessment for differentiation of TR from RN.

Level Of Evidence: 1 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2019;50:573-582.
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http://dx.doi.org/10.1002/jmri.26621DOI Listing
August 2019

Selective and super-selective C-arm based cone beam CT angiography (CBCTA) with DynaCT for CyberKnife radiosurgery planning of intracranial arteriovenous malformations (AVMs).

J Radiosurg SBRT 2018 ;5(4):305-313

Division of Radiation Oncology, University of Ottawa, Ottawa, ON, Canada.

Background: Successful radiosurgery for intracranial arteriovenous malformations (AVMs) requires accurate delineation of the nidus in 3D. Exact targeting and precise equipment is needed to achieve obliteration of the nidus while minimizing toxicity to the surrounding brain. In some micro-AVMs and poorly visible AVMs we have used cone beam CT angiography (CBCTA) with selective and super-selective angiography where a micro-catheter is advanced into the feeding arteries- to assist with nidus definition for CyberKnife radiosurgery planning.

Methods: Four patients who had AVMs inadequately visualized with MRI, MRA, CT, CTA, and dynamic CT angiography (dCTA) were identified for selective angiography (2 had super-selective angiography) for CyberKnife radiosurgery. The mean age at the time of treatment was 45 years (range: 22 - 71 years). All patients had suffered prior hemorrhage and were deemed inoperable. Super-selective angiography was done under general anesthesia to minimize motion artefact and the risk of arterial dissection. Angiography was performed using the biplane angiographic suite (ArtisQ; Siemens). Cone beam reconstructions were performed using DynaCT software. For each scan, volumetric data was acquired over 20 seconds in a single rotation of the C-arm mounted flat-panel detector cone-beam CT system. The data set was imported into the CyberKnife TPS and co-registered with the treatment planning CT, T2 MRI and Toshiba dCTA. Delineation of the AVM nidus was performed by the multi-disciplinary AVM team.

Results: There were no adverse events related to the angiography or radiosurgery treatment. CBCTA data sets created using DynaCT were accurately co-registered with the treatment planning scans in the CyberKnife treatment planning system (Multiplan). For all 4 patients, feeding arteries, draining veins and nidi were clearly visualized and used to develop radiosurgery plans. Mean nidus size was 0.45cc (range: 0.07 - 1.00cc).

Conclusions: For intracranial micro-AVMs and AVMs otherwise poorly visualized using DSA, MRA, CTA or dCTA, selective and super-selective CBCTA images (created using DynaCT) can be successfully imported into the CyberKnife TPS to assist in nidus delineation. Advancement of a micro-catheter into the feeding arteries to allow continuous contrast injection during volumetric scanning constitutes super-selective CBCTA. This technique provides superior visualization of micro-AVMs and should be utilized for radiosurgery planning of poorly visualized AVMs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255721PMC
January 2018

Design and Conduct Considerations for First-in-Human Trials.

Clin Transl Sci 2019 01 24;12(1):6-19. Epub 2018 Aug 24.

Non-Clinical and Translational Sciences, Allergan, California, USA.

A milestone step in translational science to transform basic scientific discoveries into therapeutic applications is the advancement of a drug candidate from preclinical studies to initial human testing. First-in-human (FIH) trials serve as the link to advance new promising drug candidates and are conducted primarily to determine the safe dose range for further clinical development. Cross-functional collaboration is essential to ensure efficient and successful FIH trials. The aim of this publication is to serve as a tutorial for conducting FIH trials for both small molecule and biological drug candidates with topics covering regulatory requirements, preclinical safety testing, study design considerations, safety monitoring, biomarker assessment, and global considerations. An emphasis is placed on FIH trial design considerations, including starting dose selection, study size and population, dose escalation scheme, and implementation of adaptive designs. In light of the recent revision of the European Medicines Agency (EMA) guideline on FIH trials to promote safety and mitigate risk, we also discuss new measures introduced in the guideline that impact FIH trial design.
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http://dx.doi.org/10.1111/cts.12582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342261PMC
January 2019

A Virally Encoded DeSUMOylase Activity Is Required for Cytomegalovirus Reactivation from Latency.

Cell Rep 2018 07;24(3):594-606

Institute of Immunity & Transplantation, University College London, Royal Free Campus, London NW3 2PF, UK. Electronic address:

A subset of viral genes is required for the long-term latent infection of hematopoietic cells by human cytomegalovirus (HCMV). Here, we show that a latency-associated gene product (LUNA) promotes the disruption of cellular PML bodies during latency. Mutation and inhibitor studies reveal that LUNA encodes a deSUMOylase activity responsible for this disruption. Specifically, LUNA encodes a conserved Asp-Cys-Gly motif common to all deSUMOylases. Importantly, mutation of the putative catalytic cysteine is sufficient to reverse LUNA-mediated PML dispersal and markedly reduces the efficiency of viral reactivation. The depletion of PML from cells is sufficient to rescue the reactivation of the LUNA-deficient viruses, arguing that targeting PML is an important biological role of LUNA. Finally, we demonstrate that reactivation of naturally latent HCMV is blocked by deSUMOylase inhibitors. Thus, latent HCMV primes the cellular environment for efficient reactivation via the activity of a virally encoded deSUMOylase.
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http://dx.doi.org/10.1016/j.celrep.2018.06.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077246PMC
July 2018

Anemia prevalence and incidence and red blood cell transfusion practices in aneurysmal subarachnoid hemorrhage: results of a multicenter cohort study.

Crit Care 2018 07 4;22(1):169. Epub 2018 Jul 4.

Department of Medicine (Critical Care), The Ottawa Hospital, Civic Campus Room F202, 1053 Carling Avenue, Ottawa, ON, K1Y 4E9, Canada.

Background: Whether a restrictive strategy for red blood cell (RBC) transfusion is applied to patients with aneurysmal subarachnoid hemorrhage (aSAH) is unclear. To inform the design and conduct of a future clinical trial, we sought to describe transfusion practices, hemoglobin (Hb) triggers, and predictors of RBC transfusion in patients with aSAH.

Methods: This is a retrospective cohort study of all consecutively admitted adult patients with aSAH at four tertiary care centers from January 1, 2012, to December 31, 2013. Patients were identified from hospital administrative discharge records and existing local aSAH databases. Data collection by trained abstractors included demographic data, aSAH characteristics, Hb and transfusion data, other major aSAH cointerventions, and outcomes using a pretested case report form with standardized procedures. Descriptive statistics were used to summarize data, and regression models were used to identify associations between anemia, transfusion, and other relevant predictors and outcome.

Results: A total of 527 patients met inclusion eligibility. Mean (±SD) age was 57 ± 13 years, and 357 patients (67.7%) were female. The median modified Fisher grade was 4 (IQR 3-4). Mean nadir Hb was 98 ± 20 g/L and occurred on median admission day 4 (IQR 2-11). RBC transfusion occurred in 100 patients (19.0%). Transfusion rates varied across centers (12.1-27.4%, p = 0.02). Patients received a median of 1 RBC unit (IQR 1-2) per transfusion episode and a median total of 2 units (IQR 1-4). Median pretransfusion Hb for first transfusion was 79 g/L (IQR 74-93) and did not vary substantially across centers (78-82 g/L, p = 0.37). Of patients with nadir Hb < 80 g/L, 66.3% received a transfusion compared with 2.0% with Hb nadir ≥ 100 g/L (p < 0.0001). Predictors of transfusion were history of oral anticoagulant use, anterior circulation aneurysm, neurosurgical clipping, and lower Hb. Controlling for numerous potential confounders, transfusion was not independently associated with poor outcome.

Conclusions: We observed that moderate anemia remains very common early in admission following SAH. Only one-fifth of patients with SAH received RBC transfusions, mostly in cases of significant anemia (Hb < 80 g/L), and this did not appear to be associated with outcome.
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http://dx.doi.org/10.1186/s13054-018-2089-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031110PMC
July 2018

Clinical prediction of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage.

J Neurosurg 2018 Jun 1:1-8. Epub 2018 Jun 1.

5Division of Neurology, The Ottawa Hospital, Ottawa, Ontario, Canada.

OBJECTIVEThe aim of this study was to derive a clinically applicable decision rule using clinical, radiological, and laboratory data to predict the development of delayed cerebral ischemia (DCI) in aneurysmal subarachnoid hemorrhage (aSAH) patients.METHODSPatients presenting over a consecutive 9-year period with subarachnoid hemorrhage (SAH) and at least 1 angiographically evident aneurysm were included. Variables significantly associated with DCI in univariate analysis underwent multivariable logistic regression. Using the beta coefficients, points were assigned to each predictor to establish a scoring system with estimated risks. DCI was defined as neurological deterioration attributable to arterial narrowing detected by transcranial Doppler ultrasonography, CT angiography, MR angiography, or catheter angiography, after exclusion of competing diagnoses.RESULTSOf 463 patients, 58% experienced angiographic vasospasm with an overall DCI incidence of 21%. Age, modified Fisher grade, and ruptured aneurysm location were significantly associated with DCI. This combination of predictors had a greater area under the receiver operating characteristic curve than the modified Fisher grade alone (0.73 [95% CI 0.67-0.78] vs 0.66 [95% CI 0.60-0.71]). Patients 70 years or older with modified Fisher grade 0 or 1 SAH and a posterior circulation aneurysm had the lowest risk of DCI at 1.2% (0 points). The highest estimated risk was 38% (17 points) in patients 40-59 years old with modified Fisher grade 4 SAH following rupture of an anterior circulation aneurysm.CONCLUSIONSAmong patients presenting with aSAH, this score-based clinical prediction tool exhibits increased accuracy over the modified Fisher grade alone and may serve as a useful tool to individualize DCI risk.
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http://dx.doi.org/10.3171/2018.1.JNS172715DOI Listing
June 2018