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1. Looking backward to move forward: a meta-analysis of stem cell therapy in amyotrophic lateral sclerosis

Author

Cynthia Morata-Tarifa, Garikoitz Azkona, Jonathan Glass, Letizia Mazzini, and Rosario Sanchez-Pernaute

Subjects
Medicine
Abstract

Abstract Transplantation of several types of stem cells (SC) for the treatment of amyotrophic lateral sclerosis (ALS) has been evaluated in numerous Phase I/II clinical trials with inconclusive results. Here, we conducted a meta-analysis to systematically assess the outcome of SC therapy trials which report the evolution of each patient before and after cell administration. In this way, we aimed to determine the effect of the SC intervention despite individual heterogeneity in disease progression. We identified 670 references by electronic search and 90 full-text studies were evaluated according to the eligibility criteria. Eleven studies were included comprising 220 cell-treated patients who received mesenchymal (M) SC (n = 152), neural (N) SC (n = 57), or mononuclear cells (MNC: CD34, CD117, and CD133 positive cells) (n = 11). Our analyses indicate that whereas intrathecal injection of mesenchymal stromal cells appears to have a transient positive effect on clinical progression, as measured by the ALS functional rating score, there was a worsening of respiratory function measured by forced vital capacity after all interventions. Based on current evidence, we conclude that optimal cell product and route of administration need to be determined in properly controlled preclinical models before further advancing into ALS patients. In addition, in-depth understanding of disease mechanisms in subsets of patients will help tailoring SC therapy to specific targets and increase the likelihood of improving outcomes.

Published
2021
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2. Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene

Author

Johnathan Cooper-Knock, Sai Zhang, Kevin P. Kenna, Tobias Moll, John P. Franklin, Samantha Allen, Helia Ghahremani Nezhad, Alfredo Iacoangeli, Nancy Y. Yacovzada, Chen Eitan, Eran Hornstein, Eran Ehilak, Petra Celadova, Daniel Bose, Sali Farhan, Simon Fishilevich, Doron Lancet, Karen E. Morrison, Christopher E. Shaw, Ammar Al-Chalabi, Jan H. Veldink, Janine Kirby, Michael P. Snyder, Pamela J. Shaw, Ian Blair, Naomi Wray, Matthew Kiernan, Miguel Mitne Neto, Adriano Chio, Ruben Cauchi, Wim Robberecht, Philip van Damme, Phillippe Corcia, Phillipe Couratier, Orla Hardiman, Russel McLaughlin, Marc Gotkine, Vivan Drory, Nicola Ticozzi, Vincenzo Silani, Jan Veldink, Leonard van den Berg, Mamede de Carvalho, Jesus Mora Pardina, Monica Povedano, Peter Andersen, Markus Wber, Nazli Başak, Christopher Shaw, Pamela Shaw, Karen Morrison, John Landers, and Jonathan Glass

Subjects
amyotrophic lateral sclerosis, whole-genome sequencing, CAV1, CAV2, non-coding DNA, gene enhancers, Biology (General), QH301-705.5
Abstract

Summary: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion of ALS risk variants within the non-coding genome, but further characterization has been limited by lack of appropriate tools. By designing and applying a pipeline to identify pathogenic genetic variation within enhancer elements responsible for regulating gene expression, we identify disease-associated variation within CAV1/CAV2 enhancers, which replicate in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2 expression and disrupt MLRs in patient-derived cells, and CRISPR-Cas9 perturbation proximate to a patient mutation is sufficient to reduce CAV1/CAV2 expression in neurons. Additional enrichment of ALS-associated mutations within CAV1 exons positions CAV1 as an ALS risk gene. We propose CAV1/CAV2 overexpression as a personalized medicine target for ALS.

Published
2020
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3. Protoporphyrin IX regulates peripheral benzodiazepine receptor associated protein 7 (PAP7) and divalent metal transporter 1 (DMT1) in K562 cells

Author

Yasumasa Okazaki and Jonathan Glass

Subjects
Peripheral-type benzodiazepine receptor (PBR)-associated protein 7 (PAP7), Divalent metal transporter 1 (DMT1), Peripheral-type benzodiazepine receptor (PBR), Protoporphyrin IX, Iron metabolism, Biology (General), QH301-705.5, Biochemistry, QD415-436
Abstract

Background: Protoporphyrin IX (PP IX), the immediate precursor to heme, combines with ferrous iron to make this product. The effects of exogenous PP IX on iron metabolism remain to be elucidated. Peripheral-type benzodiazepine receptor (PBR) is implicated in the transport of coproporphyrinogen into the mitochondria for conversion to PP IX. We have demonstrated that PBR-Associated Protein 7 (PAP7) bound to the Iron Responsive Element (IRE) isoform of divalent metal transporter 1 (DMT1). PP IX and PAP7 are ligands for PBR, thus, we hypothesized that PAP7 interact with PP IX via PBR. Methods: We have examined in K562 cells, which can be induced to undergo erythroid differentiation by PP IX and hemin, the effects of PP IX on the expression of PAP7 and other proteins involved in cellular iron metabolism, transferrin receptor 1 (TfR1), DMT1, ferritin heavy chain (FTH), c-Myc and C/EBPα by western blot and quantitative real time PCR analyses. Results: PP IX significantly decreased mRNA levels of DMT1 (IRE) and (non-IRE) from 4 h. PP IX markedly decreased protein levels of C/EBPα, PAP7 and DMT1. In contrast, hemin, which like PP IX also induces K562 cell differentiation, had no effect on PAP7 or DMT1 expression. Conclusion: We hypothesize that PP IX binds to PBR displacing PAP7 protein, which is then degraded, decreasing the interaction of PAP7 with DMT1 (IRE) and resulting in increased turnover of DMT1. General significance: These results suggest that exogenous PP IX disrupts iron metabolism by decreasing the protein expression levels of PAP7, DMT1 and C/EBPα.

Published
2017
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4. β2-Adrenoceptor agonists as novel, safe and potentially effective therapies for Amyotrophic lateral sclerosis (ALS)

Author

Raymond T. Bartus, Alexandre Bétourné, Anthony Basile, Bethany L. Peterson, Jonathan Glass, and Nicholas M. Boulis

Subjects
β2-Adrenoceptor agonists, Repurposing drugs, ALS, Neuroprotection, Neurorestoration, Anabolic muscle effects, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Amyotrophic lateral sclerosis (ALS) is a chronic and progressive neuromuscular disease for which no cure exists and better treatment options are desperately needed. We hypothesize that currently approved β2-adrenoceptor agonists may effectively treat the symptoms and possibly slow the progression of ALS. Although β2-agonists are primarily used to treat asthma, pharmacologic data from animal models of neuromuscular diseases suggest that these agents may have pharmacologic effects of benefit in treating ALS. These include inhibiting protein degradation, stimulating protein synthesis, inducing neurotrophic factor synthesis and release, positively modulating microglial and systemic immune function, maintaining the structural and functional integrity of motor endplates, and improving energy metabolism. Moreover, stimulation of β2-adrenoceptors can activate a range of downstream signaling events in many different cell types that could account for the diverse array of effects of these agents. The evidence supporting the possible therapeutic benefits of β2-agonists is briefly reviewed, followed by a more detailed review of clinical trials testing the efficacy of β-agonists in a variety of human neuromuscular maladies. The weight of evidence of the potential benefits from treating these diseases supports the hypothesis that β2-agonists may be efficacious in ALS. Finally, ways to monitor and manage the side effects that may arise with chronic administration of β2-agonists are evaluated. In sum, effective, safe and orally-active β2-agonists may provide a novel and convenient means to reduce the symptoms of ALS and possibly delay disease progression, affording a unique opportunity to repurpose these approved drugs for treating ALS, and rapidly transforming the management of this serious, unmet medical need.

Published
2016
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5. Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype

Author

Johnathan Cooper-Knock, Henry Robins, Isabell Niedermoser, Matthew Wyles, Paul R. Heath, Adrian Higginbottom, Theresa Walsh, Mbombe Kazoka, Project MinE ALS Sequencing Consortium, Paul G. Ince, Guillaume M. Hautbergue, Christopher J. McDermott, Janine Kirby, Pamela J. Shaw, Ahmad Al Kheifat, Ammar Al-Chalabi, Nazli Basak, Ian Blair, Annelot Dekker, Orla Hardiman, Winston Hide, Alfredo Iacoangeli, Kevin Kenna, John Landers, Russel McLaughlin, Jonathan Mill, Bas Middelkoop, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Sara Pulit, Aleksey Shatunov, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristelvan Eijk, Michael van Es, Wouter van Rheenen, Joke van Vugt, Jan Veldink, Maarten Kooyman, Jonathan Glass, Wim Robberecht, Marc Gotkine, Vivian Drory, Matthew Kiernan, Miguel Mitne Neto, Mayana Ztaz, Philippe Couratier, Philippe Corcia, Vincenzo Silani, Adriano Chio, Mamede de Carvalho, Susana Pinto, Alberto Garcia Redondo, Peter Andersen, Markus Weber, and Nicola Ticozzi

Subjects
amyotrophic lateral sclerosis, RNA binding proteins, oligogenic inheritance, C9ORF72, DNA sequencing, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development.

Published
2017
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6. The Application of Parallel Robotics to Investigate the Effect of Lumbar Bracing on Trunk Muscle Activity

Author

Gregory N. Kawchuk, Narasimha G. Prasad, Jonathan Glass, Carolyn Knight, Serena Third, and Daniel Timmermans

Subjects
Biotechnology, TP248.13-248.65, Biology (General), QH301-705.5
Abstract

Lumbar bracing is prescribed frequently for disability caused by low back pain; however, investigations into this practice demonstrate a range of patient outcomes. This inconsistency may arise from the practice of employing voluntary, single-axis trunk movements when investigating braces. Alternatively, this study employed a parallel robot to create a standardised, multi-axis testing environment. Surface electromyographic (sEMG) data were collected from the trunk of 24 asymptomatic participants, who were seated on the robot, tilted to 15°, then circumducted while attempting to maintain an upright posture. Multiple trials were performed for three randomised conditions: non-braced, soft-material brace and stiff-material brace. As expected, the sEMG activity was significantly reduced in the majority of muscle responses (201/240). Unexpectedly, a paradoxical increase in the sEMG activity was observed in 39/240 responses. While lumbar bracing reduces the sEMG activity on average, these data suggest the existence of an infrequent paradoxical response that may provide a possible explanation for the discordant results observed in previous bracing investigations.

Published
2010
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7. Design and initial results of a multi-phase randomized trial of ceftriaxone in amyotrophic lateral sclerosis.

Author

James D Berry, Jeremy M Shefner, Robin Conwit, David Schoenfeld, Myles Keroack, Donna Felsenstein, Lisa Krivickas, William S David, Francine Vriesendorp, Alan Pestronk, James B Caress, Jonathan Katz, Ericka Simpson, Jeffrey Rosenfeld, Robert Pascuzzi, Jonathan Glass, Kourosh Rezania, Jeffrey D Rothstein, David J Greenblatt, Merit E Cudkowicz, and Northeast ALS Consortium

Subjects
Medicine, Science
Abstract

Ceftriaxone increases expression of the astrocytic glutamate transporter, EAAT2, which might protect from glutamate-mediated excitotoxicity. A trial using a novel three stage nonstop design, incorporating Phases I-III, tested ceftriaxone in ALS. Stage 1 determined the cerebrospinal fluid pharmacokinetics of ceftriaxone in subjects with ALS. Stage 2 evaluated safety and tolerability for 20-weeks. Analysis of the pharmacokinetics, tolerability, and safety was used to determine the ceftriaxone dosage for Stage 3 efficacy testing.In Stage 1, 66 subjects at ten clinical sites were enrolled and randomized equally into three study groups receiving intravenous placebo, ceftriaxone 2 grams daily or ceftriaxone 4 grams daily divided BID. Participants provided serum and cerebrospinal fluid for pharmacokinetic analysis on study day 7. Participants continued their assigned treatment in Stage 2. The Data and Safety Monitoring Board (DSMB) reviewed the data after the last participants completed 20 weeks on study drug.Stage 1 analysis revealed linear pharmacokinetics, and CSF trough levels for both dosage levels exceeding the pre-specified target trough level of 1 µM (0.55 µg/mL). Tolerability (Stages 1 and 2) results showed that ceftriaxone at dosages up to 4 grams/day was well tolerated at 20 weeks. Biliary adverse events were more common with ceftriaxone but not dose-dependent and improved with ursodeoxycholic (ursodiol) therapy.The goals of Stages 1 and 2 of the ceftriaxone trial were successfully achieved. Based on the pre-specified decision rules, the DSMB recommended the use of ceftriaxone 4 g/d (divided BID) for Stage 3, which recently closed.ClinicalTrials.gov NCT00349622.

Published
2013
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8. Behavior matters--cognitive predictors of survival in amyotrophic lateral sclerosis.

Author

William T Hu, Matthew Shelnutt, Ashley Wilson, Nicole Yarab, Crystal Kelly, Murray Grossman, David J Libon, Jaffar Khan, James J Lah, Allan I Levey, and Jonathan Glass

Subjects
Medicine, Science
Abstract

It is difficult to longitudinally characterize cognitive impairment in amyotrophic lateral sclerosis (ALS) due to motor deficits, and existing instruments aren't comparable with assessments in other dementias.The ALS Brief Cognitive Assessment (ALS-BCA) was validated in 70 subjects (37 with ALS) who also underwent detailed neuropsychological analysis. Cognitive predictors for poor survival were then analyzed in a longitudinal cohort of 171 ALS patients.The ALS-BCA was highly sensitive (90%) and specific (85%) for ALS-dementia (ALS-D). ALS-D patients had shorter overall survival, primarily due to the poor survival among ALS-D patients with disinhibited or apathetic behaviors after adjusting for demographic variables, ALS site of onset, medications, and supportive measures. ALS-D without behavioral changes was not a predictor of poor survival.ALS-D can present with or without prominent behavioral changes. Cognitive screening in ALS patients should focus on behavioral changes for prognosis, while non-behavioral cognitive impairments may impact quality of life without impacting survival.

Published
2013
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9. The phenotypic radiation resistance of CD44+/CD24(-or low) breast cancer cells is mediated through the enhanced activation of ATM signaling.

Author

Hong Yin and Jonathan Glass

Subjects
Medicine, Science
Abstract

Cancer initiating cells (CIC) are stem-like cells. CIC may contribute not only to the initiation of cancer but also to cancer recurrence because of the resistance of CIC both to chemotherapy and radiation therapy. From the MCF-7 and MDA-MB231 breast cancer cell lines and primary culture of patient breast cancer cells, we isolated by flow cytometry a CIC subset of cells with the CD44(+)/CD24(-or low) phenotype. The CD44(+)/CD24(-or low) subset showed increased sphere formation and resistance to radiation compared to the non- CD44(+)/CD24(-or low) subset. The increased radiation resistance was not dependent on the result of altered non-homologous end joining (NHEJ) DNA repair activity as both NHEJ activity and expression of the various proteins involved in NHEJ were not significantly different between the CD44(+)/CD24(-or low) and non- CD44(+)/CD24(-or low) subsets. However, activation of ATM signaling was significantly increased in CD44(+)/CD24(-or low) cells compared to non- CD44(+)/CD24(-or low) cells in both from breast cancer cell lines and primary human breast cancer cells. Application of an ATM inhibitor effectively decreased the radiation resistance of CD44(+)/CD24(-or low) subset, suggesting that targeting ATM signaling may provide a new tool to eradicate stem-like CIC and abolish the radiation resistance of breast cancer.

Published
2011
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10. Effect of B7.1 costimulation on T-cell based immunity against TAP-negative cancer can be facilitated by TAP1 expression.

Author

Xiao-Lin Li, Yong-Yu Liu, David Knight, Yoshinobu Odaka, J Michael Mathis, Runhua Shi, Jonathan Glass, and Qian-Jin Zhang

Subjects
Medicine, Science
Abstract

Tumors deficient in expression of the transporter associated with antigen processing (TAP) usually fail to induce T-cell-mediated immunity and are resistant to T-cell lysis. However, we have found that introduction of the B7.1 gene into TAP-negative (TAP(-)) or TAP1-transfected (TAP1(+)) murine lung carcinoma CMT.64 cells can augment the capacity of the cells to induce a protective immune response against wild-type tumor cells. Differences in the strength of the protective immune responses were observed between TAP(-) and TAP1(+) B7.1 expressing CMT.64 cells depending on the doses of gamma-irradiated cell immunization. While mice immunized with either high or low dose of B7.1-expressing TAP1(+) cells rejected TAP(-) tumors, only high dose immunization with B7.1-expressing TAP(-) cells resulted in tumor rejection. The induced protective immunity was T-cell dependent as demonstrated by dramatically reduced antitumor immunity in mice depleted of CD8 or CD4 cells. Augmentation of T-cell mediated immune response against TAP(-) tumor cells was also observed in a virally infected tumor cell system. When mice were immunized with a high dose of gamma-irradiated CMT.64 cells infected with vaccinia viruses carrying B7.1 and/or TAP1 genes, we found that the cells co-expressing B7.1 and TAP1, but not those expressing B7.1 alone, induced protective immunity against CMT.64 cells. In addition, inoculation with live tumor cells transfected with several different gene(s) revealed that only B7.1- and TAP1-coexpressing tumor cells significantly decreased tumorigenicity. These results indicate that B7.1-provoked antitumor immunity against TAP(-) cancer is facilitated by TAP1-expression, and thus both genes should be considered for cancer therapy in the future.

Published
2009
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11. Trogocytosis of MHC-I/peptide complexes derived from tumors and infected cells enhances dendritic cell cross-priming and promotes adaptive T cell responses.

Author

Qian-Jin Zhang, Xiao-Lin Li, David Wang, Xiao-Cong Huang, J Michael Mathis, Wei-Ming Duan, David Knight, Runhua Shi, Jonathan Glass, Dong-Qing Zhang, Lea Eisenbach, and Wilfred A Jefferies

Subjects
Medicine, Science
Abstract

The transporter associated with antigen processing (TAP) and the major histocompatibility complex class I (MHC-I), two important components of the MHC-I antigen presentation pathway, are often deficient in tumor cells. The restoration of their expression has been shown to restore the antigenicity and immunogenicity of tumor cells. However, it is unclear whether TAP and MHC-I expression in tumor cells can affect the induction phase of the T cell response. To address this issue, we expressed viral antigens in tumors that are either deficient or proficient in TAP and MHC-I expression. The relative efficiency of direct immunization or immunization through cross-presentation in promoting adaptive T cell responses was compared. The results demonstrated that stimulation of animals with TAP and MHC-I proficient tumor cells generated antigen specific T cells with greater killing activities than those of TAP and MHC-I deficient tumor cells. This discrepancy was traced to differences in the ability of dendritic cells (DCs) to access and sample different antigen reservoirs in TAP and MHC-I proficient versus deficient cells and thereby stimulate adaptive immune responses through the process of cross-presentation. In addition, our data suggest that the increased activity of T cells is caused by the enhanced DC uptake and utilization of MHC-I/peptide complexes from the proficient cells as an additional source of processed antigen. Furthermore, we demonstrate that immune-escape and metastasis are promoted in the absence of this DC 'arming' mechanism. Physiologically, this novel form of DC antigen sampling resembles trogocytosis, and acts to enhance T cell priming and increase the efficacy of adaptive immune responses against tumors and infectious pathogens.

Published
2008
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12. Differential Vulnerability of Hippocampal Subfields in Primary Age-Related Tauopathy and Chronic Traumatic Encephalopathy

Author

Kurt Farrell, Megan A Iida, Jonathan D Cherry, Alicia Casella, Thor D Stein, Kevin F Bieniek, Jamie M Walker, Timothy E Richardson, Charles L White, Victor E Alvarez, Bertrand R Huber, Dennis W Dickson, Ricardo Insausti, Kristen Dams-O'Connor, Jean-Paul Vonsattel, Andy F Teich, Marla Gearing, Jonathan Glass, Juan C Troncoso, Matthew P Frosch, Bradley T Hyman, Melissa E Murray, Johannes Attems, Margaret E Flanagan, Qinwen Mao, M-Marsel Mesulam, Sandra Weintraub, Randy L Woltjer, Thao Pham, Julia Kofler, Julie A Schneider, Lei Yu, Dushyant P Purohit, Vahram Haroutunian, Patrick R Hof, Sam Gandy, Mary Sano, Thomas G Beach, Wayne Poon, Claudia H Kawas, María M Corrada, Robert A Rissman, Jeff Metcalf, Sara Shuldberg, Bahar Salehi, Peter T Nelson, John Q Trojanowski, Edward B Lee, David A Wolk, Corey T McMillan, C Dirk Keene, Caitlin S Latimer, Thomas J Montine, Gabor G Kovacs, Mirjam I Lutz, Peter Fischer, Richard J Perrin, Nigel J Cairns, Ann C McKee, and John F Crary

Subjects
Cellular and Molecular Neuroscience, Neurology, Tauopathies, Humans, Neurofibrillary Tangles, tau Proteins, Neurology (clinical), General Medicine, Hippocampus, Pathology and Forensic Medicine, Chronic Traumatic Encephalopathy
Abstract

Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomically with primary age-related tauopathy (PART), an age-related tauopathy characterized by Alzheimer disease-like tau pathology in the hippocampus devoid of amyloid plaques. We measured p-tau burden using positive-pixel counts on immunohistochemically stained and neuroanatomically segmented hippocampal tissue. Subjects with CTE had a higher total p-tau burden than PART subjects in all sectors (p = 0.005). Within groups, PART had significantly higher total p-tau burden in CA1/subiculum compared to CA3 (p = 0.02) and CA4 (p = 0.01) and total p-tau burden in CA2 trended higher than CA4 (p = 0.06). In CTE, total p-tau burden in CA1/subiculum was significantly higher than in the dentate gyrus; and CA2 also trended higher than dentate gyrus (p = 0.01, p = 0.06). When controlling for p-tau burden across the entire hippocampus, CA3 and CA4 had significantly higher p-tau burden in CTE than PART (p lt; 0.0001). These data demonstrate differences in hippocampal p-tau burden and regional distribution in CTE compared to PART that might be helpful in differential diagnosis and reveal insights into disease pathogenesis.

Published
2023

13. Supplementary Figures 1-2 from Comparison of radiosensitizing effects of the mammalian target of rapamycin inhibitor CCI-779 to cisplatin in experimental models of head and neck squamous cell carcinoma

Author

Cherie-Ann O. Nathan, Jonathan Glass, Federico Ampil, John Kai Siung Chang, Gloria Caldito, Fleurette Abreo, Kavita M. Pattani, Xiaohua Rong, Youhua Rong, and Oleksandr Ekshyyan

Abstract

Supplementary Figures 1-2 from Comparison of radiosensitizing effects of the mammalian target of rapamycin inhibitor CCI-779 to cisplatin in experimental models of head and neck squamous cell carcinoma

Published
2023
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14. Data from Comparison of radiosensitizing effects of the mammalian target of rapamycin inhibitor CCI-779 to cisplatin in experimental models of head and neck squamous cell carcinoma

Author

Cherie-Ann O. Nathan, Jonathan Glass, Federico Ampil, John Kai Siung Chang, Gloria Caldito, Fleurette Abreo, Kavita M. Pattani, Xiaohua Rong, Youhua Rong, and Oleksandr Ekshyyan

Abstract

To determine if the mammalian target of rapamycin (mTOR) inhibitor CCI-779 can sensitize head and neck squamous cell carcinoma (HNSCC) to radiotherapy (XRT) and compare the radiosensitizing effects to cisplatin with its known considerable toxicity. Radiosensitizing effects of CCI-779 were assayed on HNSCC cell lines in vitro. CCI-779 (5 mg/kg), cisplatin (1 mg/kg), and XRT (2 Gy) alone and in combination were evaluated for antitumor activity in mice bearing FaDu and SCC40 xenografts. Effects of CCI-779 on radiation-induced activation of the Akt/mTOR pathway were analyzed. Although CCI-779 did not sensitize HNSCC cells to ionizing radiation in vitro, combination of CCI-779 and XRT significantly augmented the in vivo tumor growth-inhibitory effects of XRT and CCI-779 (P < 0.05). In addition, CCI-779 + XRT suppressed tumor growth more effectively than cisplatin + XRT (P < 0.05). CCI-779 + XRT significantly improved survival compared with XRT alone in both cisplatin-sensitive FaDu (P < 0.01) and cisplatin-resistant SCC40 (P < 0.05) xenograft mice. There were no additional benefits of adding cisplatin to CCI-779 + XRT. CCI-779 significantly attenuated irradiation-induced up-regulation of the mTOR pathway, increased apoptosis and displayed potent antiangiogenic activity in FaDu xenografts that was further enhanced by its combination with XRT (P < 0.05), which may explain the mechanism of its selective radiosensitizing effects in vivo and not in vitro. Antitumor activity of XRT was enhanced when combined with CCI-779 in HNSCC xenograft model. CCI-779 + XRT showed antitumor activity superior to conventional chemoradiotherapy with cisplatin. These results pave the way for clinical trials using molecular targeted therapy with CCI-779 in combination with XRT for HNSCC treatment. [Mol Cancer Ther 2009;8(8):2255–65]

Published
2023
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15. Renal stones

Author

Jonathan Glass

Abstract

Percutaneous surgery is the treatment of choice in the management of large and staghorn stones of the urinary tract. Imaging with preoperative computed tomography scanning is mandatory. The procedure has undergone a number of modifications over the past 40 years since first being described by Alken and colleagues in 1982. Developments have included the challenge as to whether prone is the best position, miniaturization of the access tract, the use of multiple tracts, the abandonment of the post-procedure nephrostomy, and the combination of simultaneous flexible ureteroscopy with percutaneous nephrolithotomy. It is, however, a complex procedure with a significant complication rate including postoperative bleeding and sepsis, particularly with staghorn stones. This case illustrates the use of percutaneous surgery in a patient with a staghorn stone complicated by a postoperative bleed managed by super-selective arterial embolization.

Published
2023
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17. Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

Author

Robert C. Bucelli, Manjit McNeill, Shafeeq Ladha, Angela Genge, Stephanie Fradette, Ivan Nestorov, John Ravits, Philip Van Damme, Roger Lane, Christopher J McDermott, Jonathan Glass, Merit Cudkowicz, Laura Fanning, C. Frank Bennett, Heiko Runz, Ih Chang, Hani Houshyar, Toby A. Ferguson, Alfred Sandrock, Alan Pestronk, Danielle Graham, Timothy M. Miller, Randall G. Trudell, Nazem Atassi, Peter M. Andersen, François Salachas, Nicholas J. Maragakis, Albert L. Ludolph, Pamela J. Shaw, Lorne Zinman, and Alexander McCampbell

Subjects
Messenger RNA, Mutation, biology, business.industry, Oligonucleotide, animal diseases, SOD1, nutritional and metabolic diseases, General Medicine, 030204 cardiovascular system & hematology, Intrathecal, medicine.disease_cause, Molecular biology, nervous system diseases, Superoxide dismutase, 03 medical and health sciences, 0302 clinical medicine, nervous system, Antisense oligonucleotides, Protein biosynthesis, biology.protein, Medicine, 030212 general & internal medicine, business
Abstract

Background Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administratio...

Published
2020
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18. ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain of function

Author

Devesh C. Pant, Janani Parameswaran, Lu Rao, Liang Shi, Ganesh Chilukuri, Zachary T. McEachin, Jonathan Glass, Gary J. Bassell, Arne Gennerich, and Jie Jiang

Abstract

Mutations in the human kinesin family member 5A (KIF5A) gene were recently identified as a genetic cause of amyotrophic lateral sclerosis (ALS). Several KIF5A ALS variants cause exon 27 skipping and produce motor proteins with an altered C-terminal tail (referred to as ΔExon27). However, the underlying pathogenic mechanism is still unknown. In this study, we performed a comprehensive analysis of ΔExon27 at the single-molecule, cellular, and organism levels. Our results show that ΔExon27 is prone to form cytoplasmic aggregates and is neurotoxic. The mutation relieves motor autoinhibition and increases motor self-association, leading to drastically enhanced processivity on microtubules. Finally, ectopic expression of ΔExon27 in Drosophila melanogaster causes wing defects, motor impairment, paralysis and premature death. Our results suggest gain of function as an underlying disease mechanism in KIF5A-associated ALS.

Published
2022
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19. Scientific truth or myth

Author

Jonathan Glass

Subjects
General Medicine
Abstract

Our Editor reflects on the previous 'truths' that the surgical community once held true, and how these evolve with progress and technology.

Published
2023
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20. Erratum to 'Effect of Simulation-based Training on Surgical Proficiency and Patient Outcomes: A Randomised Controlled Clinical and Educational Trial' [Eur Urol 2022;81:385–393]

Author

Abdullatif Aydın, Kamran Ahmed, Takashige Abe, Nicholas Raison, Mieke Van Hemelrijck, Hans Garmo, Hashim U. Ahmed, Furhan Mukhtar, Ahmed Al-Jabir, Oliver Brunckhorst, Nobuo Shinohara, Wei Zhu, Guohua Zeng, John P. Sfakianos, Mantu Gupta, Ashutosh Tewari, Ali Serdar Gözen, Jens Rassweiler, Andreas Skolarikos, Thomas Kunit, Thomas Knoll, Felix Moltzahn, George N. Thalmann, Andrea G. Lantz Powers, Ben H. Chew, Kemal Sarica, Muhammad Shamim Khan, Prokar Dasgupta, Umair Baig, Haleema Aya, Mohammed Husnain Iqbal, Francesca Kum, Matthew Bultitude, Jonathan Glass, Azhar Khan, Jonathan Makanjuola, John E. McCabe, Azi Samsuddin, Craig McIlhenny, James Brewin, Shashank Kulkarni, Sikandar Khwaja, Waliul Islam, Howard Marsh, Taher Bhat, Benjamin Thomas, Mark Cutress, Fadi Housami, Timothy Nedas, Timothy Bates, Rono Mukherjee, Stuart Graham, Matthieu Bordenave, Charles Coker, Shwan Ahmed, Andrew Symes, Robert Calvert, Ciaran Lynch, Ronan Long, Jacob M. Patterson, Nicholas J. Rukin, Shahid A. Khan, Ranan Dasgupta, Stephen Brown, Ben Grey, Waseem Mahmalji, Wayne Lam, Walter Scheitlin, Norbert Saelzler, Marcel Fiedler, Shuhei Ishikawa, Yoshihiro Sasaki, Ataru Sazawa, Yuichiro Shinno, Tango Mochizuki, Jan Peter Jessen, Roland Steiner, Gunnar Wendt-Nordahl, Nabil Atassi, Heiko Kohns, Ashley Cox, Ricardo Rendon, Joseph Lawen, Greg Bailly, and Trevor Marsh

Subjects
Urology
Published
2022
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21. Extra-Anatomic Stents in Ureteric Obstruction: Our Experience

Author

Andrew J. Dickinson, Jonathan Glass, Marios Hadjipavlou, James J Y Chong, Francesca Kum, Jemma Hale, and Wasim Mahmalji

Subjects
Male, Risk, medicine.medical_specialty, Urology, medicine.medical_treatment, Urinary Bladder, 030232 urology & nephrology, Comorbidity, Constriction, Pathologic, Urinary Diversion, urologic and male genital diseases, Ureteric obstruction, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Neoplasms, Humans, Medicine, In patient, Perioperative Period, Aged, Aged, 80 and over, business.industry, Stent, Middle Aged, Surgery, Treatment Outcome, surgical procedures, operative, Fluoroscopy, 030220 oncology & carcinogenesis, Quality of Life, Drainage, Female, Stents, Ureter, business, Nephrotomy, Ureteral Obstruction
Abstract

To present our experience of the Detour extra-anatomic stent (EAS; Porges-Coloplast, Denmark) to bypass ureteric obstruction. Use of the EAS is indicated in patients with complex ureteric strictures or malignant disease, where long-term nephrostomy drainage is undesirable.Between December 2001 and October 2017, 20 Detour EAS were implanted into 13 patients. The primary indication was ureteric obstruction or injury secondary to metastatic malignancy, or from treatment for malignancy. Five patients required bilateral EAS, with two patients having bilateral EAS following initial unilateral insertion. In 11 patients, the stent was inserted into their bladder, with 2 diverted into a double-barreled stoma. The mean age at the time of implantation was 64 years (range: 50-83 years), and the median follow-up was 12 months (range: 1.5-42 months).Four patients required stent revision for urinary leaks, and two developed recurrent urinary tract infections in their stent requiring intravenous antibiotics. All EAS continued to drain successfully following treatment or revision. One patient died due to complications from dislodgement of the stent, leading to laparotomy and intra-abdominal sepsis. Seven patients died due to progression of metastatic malignant disease, and the Detour EAS was functioning in all seven at time of death. The remaining five patients are well with functioning Detour EAS.The Detour EAS system provides a suitable alternative option for urinary diversion, affording a good quality of life to carefully selected patients with multiple comorbidities and malignant disease.

Published
2019
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22. Genome-wide association study and functional validation implicates JADE1 in tauopathy

Author

Kurt Farrell, SoongHo Kim, Natalia Han, Megan A. Iida, Elias Gonzalez, Marcos Otero-Garcia, Jamie Walker, Tim Richardson, Alan E. Renton, Shea J. Andrews, Brian Fulton-Howard, Jack Humphrey, Ricardo A. Vialle, Kathryn R. Bowles, Kristen Whitney, Diana K. Dangoor, Edoardo Marcora, Marco M. Hefti, Alicia Casella, Cheick Sissoko, Manav Kapoor, Gloriia Novikova, Evan Udine, Garrett Wong, Weijing Tang, Tushar Bhangale, Julie Hunkapiller, Gai Ayalon, Rob Graham, Jonathan D. Cherry, Etty Cortes, Valeriy Borukov, Ann C. McKee, Thor D. Stein, Jean-Paul Vonsattel, Andy F. Teich, Marla Gearing, Jonathan Glass, Juan C. Troncoso, Matthew P. Frosch, Bradley T. Hyman, Dennis W. Dickson, Melissa E. Murray, Johannes Attems, Margaret E. Flanagan, Qinwen Mao, M-Marsel Mesulam, Sandra Weintraub, Randy Woltjer, Thao Pham, Julia Kofler, Julie A. Schneider, Lei Yu, Dushyant P. Purohit, Vahram Haroutunian, Patrick R. Hof, Sam Gandy, Mary Sano, Thomas G. Beach, Wayne Poon, Claudia Kawas, María Corrada, Robert A. Rissman, Jeff Metcalf, Sara Shuldberg, Bahar Salehi, Peter T. Nelson, John Q. Trojanowski, Edward B. Lee, David A. Wolk, Corey T. McMillan, Dirk C. Keene, Thomas J. Montine, Gabor G. Kovacs, Mirjam I. Lutz, Peter Fischer, Richard J. Perrin, Nigel Cairns, Erin E. Franklin, Herbert T. Cohen, Maria Inmaculada Cobos Sillero, Bess Frost, Towfique Raj, Alison Goate, Charles L. White, and John F. Crary

Subjects
medicine, Neurofibrillary tangle, Genome-wide association study, Single-nucleotide polymorphism, Tauopathy, Alzheimer's disease, Biology, medicine.disease, Molecular biology, Phenotype, Genetic association, Progressive supranuclear palsy
Abstract

Primary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration.

Published
2021
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23. A time for change

Author

Jonathan Glass

Subjects
General Medicine
Abstract

Our editor explores the cost of mandatory training in the NHS and how this affects surgeons.

Published
2022
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24. Effect of simulation-based training on surgical proficiency and patient outcomes: A randomised controlled clinical and educational trial

Author

Abdullatif Aydın, Kamran Ahmed, Takashige Abe, Nicholas Raison, Mieke Van Hemelrijck, Hans Garmo, Hashim U. Ahmed, Furhan Mukhtar, Ahmed Al-Jabir, Oliver Brunckhorst, Nobuo Shinohara, Wei Zhu, Guohua Zeng, John P. Sfakianos, Mantu Gupta, Ashutosh Tewari, Ali Serdar Gözen, Jens Rassweiler, Andreas Skolarikos, Thomas Kunit, Thomas Knoll, Felix Moltzahn, George N. Thalmann, Andrea G. Lantz Powers, Ben H. Chew, Kemal Sarica, Muhammad Shamim Khan, Prokar Dasgupta, Umair Baig, Haleema Aya, Mohammed Husnain Iqbal, Francesca Kum, Matthew Bultitude, Jonathan Glass, Azhar Khan, Jonathan Makanjuola, John E. McCabe, Azi Samsuddin, Craig McIlhenny, James Brewin, Shashank Kulkarni, Sikandar Khwaja, Waliul Islam, Howard Marsh, Taher Bhat, Benjamin Thomas, Mark Cutress, Fadi Housami, Timothy Nedas, Timothy Bates, Rono Mukherjee, Stuart Graham, Matthieu Bordenave, Charles Coker, Shwan Ahmed, Andrew Symes, Robert Calvert, Ciaran Lynch, Ronan Long, Jacob M. Patterson, Nicholas J. Rukin, Shahid A. Khan, Ranan Dasgupta, Stephen Brown, Ben Grey, Waseem Mahmalji, Wayne Lam, Walter Scheitlin, Norbert Saelzler, Marcel Fiedler, Shuhei Ishikawa, Yoshihiro Sasaki, Ataru Sazawa, Yuichiro Shinno, Tango Mochizuki, Jan Peter Jessen, Roland Steiner, Gunnar Wendt-Nordahl, Nabil Atassi, Heiko Kohns, Ashley Cox, Ricardo Rendon, Joseph Lawen, Greg Bailly, Trevor Marsh, and Tıp Fakültesi

Subjects
medicine.medical_specialty, Urology, law.invention, Simulation training, Randomized controlled trial, law, Medicine, Humans, Training, Computer Simulation, Technical skills, Patient summary, Simulation based, Simulation Training, business.industry, Hazard ratio, Internship and Residency, Confidence interval, Initial phase, Physical therapy, Proficiency, Surgery, Clinical Competence, business, Learning Curve, Simulation
Abstract

Background: It is hypothesised that simulation enhances progression along the initial phase of the surgical learning curve. Objective: To evaluate whether residents undergoing additional simulation, compared to conventional training, are able to achieve proficiency sooner with better patient outcomes. Design, setting, and participants: This international, multicentre, randomised controlled trial recruited 94 urology residents with experience of zero to ten procedures and no prior exposure to simulation in ureterorenoscopy, selected as an index procedure. Intervention: Participants were randomised to simulation or conventional operating room training, as is the current standard globally, and followed for 25 procedures or over 18 mo. Outcome measurements and statistical analysis: The number of procedures required to achieve proficiency, defined as achieving a score of ≥28 on the Objective Structured Assessment of Technical Skill (OSATS) scale over three consecutive operations, was measured. Surgical complications were evaluated as a key secondary outcome. This trial is registered at www.isrctn.com as ISCRTN 12260261. Results and limitations: A total of 1140 cases were performed by 65 participants, with proficiency achieved by 21 simulation and 18 conventional participants over a median of eight and nine procedures, respectively (hazard ratio [HR] 1.41, 95% confidence interval [CI] 0.72–2.75). More participants reached proficiency in the simulation arm in flexible ureterorenoscopy, requiring a lower number of procedures (HR 0.89, 95% CI 0.39–2.02). Significant differences were observed in overall comparison of OSATS scores between the groups (mean difference 1.42, 95% CI 0.91–1.92; p < 0.001), with fewer total complications (15 vs 37; p = 0.003) and ureteric injuries (3 vs 9; p < 0.001) in the simulation group. Conclusions: Although the number of procedures required to reach proficiency was similar, simulation-based training led to higher overall proficiency scores than for conventional training. Fewer procedures were required to achieve proficiency in the complex form of the index procedure, with fewer serious complications overall. Patient summary: This study investigated the effect of simulation training in junior surgeons and found that it may improve performance in real operating settings and reduce surgical complications for complex procedures.

Published
2021

25. Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for

Author

Timothy, Miller, Merit, Cudkowicz, Pamela J, Shaw, Peter M, Andersen, Nazem, Atassi, Robert C, Bucelli, Angela, Genge, Jonathan, Glass, Shafeeq, Ladha, Albert L, Ludolph, Nicholas J, Maragakis, Christopher J, McDermott, Alan, Pestronk, John, Ravits, François, Salachas, Randall, Trudell, Philip, Van Damme, Lorne, Zinman, C Frank, Bennett, Roger, Lane, Alfred, Sandrock, Heiko, Runz, Danielle, Graham, Hani, Houshyar, Alexander, McCampbell, Ivan, Nestorov, Ih, Chang, Manjit, McNeill, Laura, Fanning, Stephanie, Fradette, and Toby A, Ferguson

Subjects
Adult, Male, Dose-Response Relationship, Drug, Leukocytosis, Amyotrophic Lateral Sclerosis, Vital Capacity, Headache, Intermediate Filaments, Oligonucleotides, Middle Aged, Oligonucleotides, Antisense, Superoxide Dismutase-1, Double-Blind Method, Mutation, Disease Progression, Humans, Female, Injections, Spinal
Abstract

Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due toWe conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due toA total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose.In adults with ALS due to

Published
2020

26. Flexible ureterorenoscopy to treat upper urinary tract stones in children

Author

Massimo Garriboli, Jonathan Glass, Arash Taghizadeh, Ahmed Suliman, and Tariq Burki

Subjects
Male, Nephrology, medicine.medical_specialty, Ureteral Calculi, Adolescent, Flexible ureterorenoscopy, Urology, medicine.medical_treatment, 030232 urology & nephrology, Aftercare, Patient Readmission, Kidney Calculi, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, Internal medicine, Ureteroscopy, medicine, Humans, Child, Retrospective Studies, Upper urinary tract, integumentary system, medicine.diagnostic_test, business.industry, Significant difference, Infant, Stent, Surgery, Treatment Outcome, Upper tract, Child, Preschool, Ureteroscopes, Female, Multiple calculi, business
Abstract

Development of surgical expertise and technology has affected the way renal tract stones are treated. Our hypothesis was that flexible ureteroscopy (FURS) for upper tract stones in children produces good results. Our outcomes were reviewed. A retrospective case note review was performed for children with upper tract calculi who were treated by FURS. There were 56 stone episodes in 36 patients. Median age was 10.6 years. Stones were 3-23 mm (median 8 mm); 64.3% had multiple calculi. Median follow-up was for 17.1 months. After the first FURS there was stone clearance in 42/56 (75%). Although there were no immediate complications, two required re-admission; one with stent symptoms, the other with urinary infection. A second FURS was performed in 11, bringing the cumulative clearance to 89%, although this was often done as "another look" before stent removal. There was no statistically significant difference in stone clearance after first FURS for those with single stones (81.0%) compared to those with multiple stones (72.2%). Clearance rates of more than 70% after first FURS were achieved with stones of up to 17 mm. Unexpected disease was found and treated during FURS in 9 (16.1%) children. FURS is safe in children and good clearance rates are achieved. Multiple stones at different sites may be treated during the same treatment. In addition, FURS allows diagnosis and treatment of unexpected problems.

Published
2018
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27. Winter resolve

Author

Jonathan Glass

Subjects
General Medicine
Abstract

We must endeavour to reduce waiting times and improve patient care.

Published
2022
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31. Percutaneous nephrolithotomy access by urologist or interventional radiologist: practice and outcomes in the UK

Author

Neil Burgess, Jonathan Glass, James N. Armitage, Sarah Fowler, Stuart Irving, Oliver Wiseman, William Finch, and John Withington

Subjects
medicine.medical_specialty, Percutaneous, Urology, medicine.medical_treatment, Stone free, Treatment outcome, 030232 urology & nephrology, Radiology, Interventional, Collection system, Kidney Calculi, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Practice Patterns, Physicians', Percutaneous nephrolithotomy, Nephrostomy, Percutaneous, medicine.diagnostic_test, business.industry, Interventional radiology, Length of Stay, United Kingdom, Surgery, Treatment Outcome, 030220 oncology & carcinogenesis, Radiology, business, Complication
Abstract

Introduction and Objective Obtaining percutaneous access to the renal collecting system is fundamental to safe and effective percutaneous nephrolithotomy (PCNL). Practice varies between countries, hospitals and individual surgeons as to whether access is obtained by a urologist or an interventional radiologist (IR). We compared outcomes of urologist versus IR tracts in the contemporary UK setting. Patients and Methods Data submitted to the British Association of Urological Surgeons (BAUS) PCNL data registry between 2009 and 2015 were analysed according to whether access was obtained by a urologist or an IR. We compared access success, number and type of tracts and perceived and actual difficulty of access. Post-operative outcomes, including stone free rates, lengths of stay and complications including transfusion rates were also compared. Results Overall, percutaneous renal access was undertaken by an IR in 3,453 of 5,211 procedures (66.3%); this rate appeared stable over the entire study period, for all categories of stone complexity and in cases where there was predicted or actual difficulty with access. Only 1% of procedures were abandoned because of failed access and this rate was identical in each group. IRs performed more multiple tract access than urologists (6.8% vs 5.1%, p=0.02), but similar rates of supracostal punctures (8.2% vs 9.2%, p=0.23). IRs used ultrasound more commonly than urologists to guide access (56.6% vs. 21.7%, p=0.0001). There were no significant differences in complication rates, lengths of stay or stone free rates. Conclusions Our findings suggest that favourable PCNL outcomes may be expected where access is obtained by either a urologist or IR, assuming that they have received the appropriate training and that they are skilled and proficient in the procedure This article is protected by copyright. All rights reserved.

Published
2017
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32. The heart sink doctor

Author

Jonathan Glass

Subjects
geography, geography.geographical_feature_category, business.industry, Medicine, General Medicine, Medical emergency, business, medicine.disease, Sink (geography)
Abstract

Much has been written about so called “heart sink” patients, but Jonathan Glass says what doctors need to avoid is becoming the heart sink doctor

Published
2019

33. Development and content validation of the percutaneous nephrolithotomy assessment score

Author

Kamran Ahmed, Andreas Skolarikos, Jonathan Glass, Kate Quirke, Jonathan Makanjuola, Abdullatif Aydin, Oliver Wiseman, Muhammad Shamim Khan, Prokar Dasgupta, Azhar Khan, Jake Patterson, Howard Marsh, Bhaskar K. Somani, Samih Al-Hayek, Matthew Bultitude, Kemal Sarica, and Tıp Fakültesi

Subjects
Content validation, medicine.medical_specialty, Operating Rooms, Urology, medicine.medical_treatment, Healthcare Failure Mode, 030232 urology & nephrology, Nephrolithotomy, Percutaneous, 03 medical and health sciences, Kidney Calculi, 0302 clinical medicine, Content validity, medicine, Training, Humans, Medical physics, Prospective Studies, Percutaneous nephrolithotomy, business.industry, Percutaneous Nephrolithotomy, Checklist, Assessment Tool, 030220 oncology & carcinogenesis, Curriculum, Single point, business, Failure mode and effects analysis
Abstract

Objectives To develop and content validate a percutaneous nephrolithotomy assessment score, taking into consideration the procedure-specific risks. Methods This prospective international study utilized the Healthcare Failure Mode and Effect Analysis to systematically outline percutaneous nephrolithotomy and failure modes for each step. A total of 25 h was spent observing percutaneous nephrolithotomy carried out by six expert surgeons. Hazard analysis scoring was carried out by 11 experts. It was determined if the steps were single point weaknesses. Single point weaknesses and those assigned a hazard score ≥4 were included in the percutaneous nephrolithotomy assessment score. The tool was then content validated by 16 experts from 10 countries. Results Application of the Healthcare Failure Mode and Effect Analysis identified 64 failure modes; 37 failure modes had a hazard score ≥4. After adaptations based on expert feedback the final percutaneous nephrolithotomy assessment score was developed containing 10 phases, 21 processes and 47 subprocesses. All participants agreed that the tool contained pertinent procedural steps. Conclusions This study has developed and shown the international content validity of a novel percutaneous nephrolithotomy assessment score. The tool can be utilized in modular operating room training to quantify operator progress, and can be used in conjunction with other modules as part of a complete percutaneous nephrolithotomy curriculum for trainees.

Published
2019

34. A state of chassis

Author

Jonathan Glass

Subjects
Chassis, Computer science, General Medicine, State (computer science), Automotive engineering
Published
2021
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37. Early inspirations

Author

Jonathan Glass

Subjects
General Medicine
Abstract

The value of surgical training must be preserved, now and in the future.

Published
2020
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38. Seasonal changes

Author

Jonathan Glass

Subjects
General Medicine
Abstract

We turn our focus to the challenges, changes and choices faced by trainees.

Published
2020
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39. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, null Shankaracharya, Bradley N. Smith, Giuseppe Marangi, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, Luigi Ferrucci, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, Aaron D. Gitler, Tim Harris, Richard M. Myers, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael C. Zody, Julia Kaye, Steven Finkbeiner, Stacia K. Wyman, Alex LeNail, Leandro Lima, Ernest Fraenkel, Clive N. Svendsen, Leslie M. Thompson, Jennifer E. Van Eyk, James D. Berry, Timothy M. Miller, Stephen J. Kolb, Merit Cudkowicz, Emily Baxi, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hisham Hamdalla, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H. Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik P. Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S. Mora, Vivian E. Drory, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Orla Hardiman, Kelly L. Williams, Jennifer A. Fifita, Garth A. Nicholson, Ian P. Blair, Guy A. Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Ekaterina Rogaeva, Lorne Zinman, Lyle W. Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, William Camu, John Q. Trojanowski, Vivianna M. Van Deerlin, Robert H. Brown, Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone, Pentti Tienari, Vincenzo Silani, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor, John E. Landers, Isabella Simone, Giancarlo Logroscino, Ilaria Bartolomei, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Stefania Tranquilli, Stefania Cuccu, Daniela Corongiu, Maurizio Melis, Antonio Milia, Francesco Marrosu, Maria Giovanna Marrosu, Gianluca Floris, Antonino Cannas, Gianluigi Mancardi, Paola Origone, Paola Mandich, Sebastiano Cavallaro, Kalliopi Marinou, Riccardo Sideri, Silvana Penco, Lorena Mosca, Giuseppe Lauria Pinter, Massimo Corbo, Paola Carrera, Nicola Fini, Antonio Fasano, Lucio Tremolizzo, Alessandro Arosio, Carlo Ferrarese, Gioacchino Tedeschi, Maria Rosaria Monsurrò, Giovanni Piccirillo, Cinzia Femiano, Anna Ticca, Enzo Ortu, Rossella Spataro, Tiziana Colletti, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Marialuisa Santarelli, Antonio Petrucci, Maura Pugliatti, Angelo Pirisi, Leslie D. Parish, Patrizia Occhineri, Fabio Giannini, Claudia Ricci, Michele Benigni, Tea B. Cau, Daniela Loi, Cristina Moglia, Maura Brunetti, Marco Barberis, Gabriella Restagno, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Canosa, Antonio Ilardi, Umberto Manera, Maurizio Grassano, Raffaella Tanel, Fabrizio Pisano, Neil A. Shneider, Stephen Goutman, Siddharthan Chandran, Suvankar Pal, George Manousakis, Stanley H. Appel, Ericka Simpson, Leo Wang, Summer Gibson, Richard Bedlack, David Lacomis, Dhruv Sareen, Alexander Sherman, Lucie Bruijn, Michelle Penny, Andrew S. Allen, Stanley Appel, Richard S. Bedlack, Braden E. Boone, Robert Brown, John P. Carulli, Alessandra Chesi, Wendy K. Chung, Elizabeth T. Cirulli, Gregory M. Cooper, Julien Couthouis, Aaron G. Day-Williams, Patrick A. Dion, Yujun Han, Sebastian D. Hayes, Angela L. Jones, Jonathan Keebler, Brian J. Krueger, Brittany N. Lasseigne, Shawn E. Levy, Yi-Fan Lu, Tom Maniatis, Slavé Petrovski, Alya R. Raphael, Zhong Ren, Katherine B. Sims, John F. Staropoli, Lindsay L. Waite, Quanli Wang, Jack R. Wimbish, Winnie W. Xin, Justin Kwan, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Noah Zaitlen, Gregory A. Cox, Steve Finkbeiner, Efthimios Dardiotis, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos A. Patsopoulos, Joshua Dubnau, Avindra Nath, Stacia Wyman, Alexander LeNail, Jenny Van Eyk, Stephan Züchner, Rebecca Schule, Jacob McCauley, Sumaira Hussain, Anne Cooley, Marielle Wallace, Christine Clayman, Richard Barohn, Jeffrey Statland, John Ravits, Andrea Swenson, Carlayne Jackson, Jaya Trivedi, Shaida Khan, Jonathan Katz, Liberty Jenkins, Ted Burns, Kelly Gwathmey, James Caress, Corey McMillan, Lauren Elman, Erik Pioro, Jeannine Heckmann, Yuen So, David Walk, Samuel Maiser, Jinghui Zhang, Fabiola De Marchi, Stefania Corti, Mauro Ceroni, Gabriele Siciliano, Massimiliano Filosto, Maurizio Inghilleri, Silvia Peverelli, Claudia Colombrita, Barbara Poletti, Luca Maderna, Roberto Del Bo, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Viviana Pensato, Barbara Castellotti, Vincent Meininger, Gérard Besson, Emmeline Lagrange, Pierre Clavelou, Nathalie Guy, Philippe Couratier, Patrick Vourch, Véronique Danel, Emilien Bernard, Gwendal Lemasson, Ahmad Al Kheifat, Peter Andersen, Adriano Chio, Jonathan Cooper-Knock, Annelot Dekker, Vivian Drory, Alberto Garcia Redondo, Marc Gotkine, Winston Hide, Alfredo Iacoangeli, Jonathan Glass, Kevin Kenna, Matthew Kiernan, John Landers, Russell McLaughlin, Jonathan Mill, Miguel Mitne Neto, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Susana Pinto, Sara Pulit, Pamela Shaw, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristel van Eijk, Michael van Es, Joke van Vugt, Jan Veldink, Mayana Zatz, Denis C. Bauer, Natalie A. Twine, Department of Neurosciences, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Clinicum, Research Programme for Molecular Neurology, University of Helsinki, Medicum, Department of Pathology, HUS Neurocenter, Nicolas A., Kenna K.P., Renton A.E., Ticozzi N., Faghri F., Chia R., Dominov J.A., Kenna B.J., Nalls M.A., Keagle P., Rivera A.M., van Rheenen W., Murphy N.A., van Vugt J.J.F.A., Geiger J.T., Van der Spek R.A., Pliner H.A., Shankaracharya, Smith B.N., Marangi G., Topp S.D., Abramzon Y., Gkazi A.S., Eicher J.D., Kenna A., Logullo F.O., Simone I.L., Logroscino G., Salvi F., Bartolomei I., Borghero G., Murru M.R., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M.G., Floris G., Cannas A., Capasso M., Caponnetto C., Mancardi G., Origone P., Mandich P., Conforti F.L., Cavallaro S., Mora G., Marinou K., Sideri R., Penco S., Mosca L., Lunetta C., Pinter G.L., Corbo M., Riva N., Carrera P., Volanti P., Mandrioli J., Fini N., Fasano A., Tremolizzo L., Arosio A., Ferrarese C., Trojsi F., Tedeschi G., Monsurro M.R., Piccirillo G., Femiano C., Ticca A., Ortu E., La Bella V., Spataro R., Colletti T., Sabatelli M., Zollino M., Conte A., Luigetti M., Lattante S., Santarelli M., Petrucci A., Pugliatti M., Pirisi A., Parish L.D., Occhineri P., Giannini F., Battistini S., Ricci C., Benigni M., Cau T.B., Loi D., Calvo A., Moglia C., Brunetti M., Barberis M., Restagno G., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Canosa A., Ilardi A., Manera U., Grassano M., Tanel R., Pisano F., Mazzini L., Messina S., D'Alfonso S., Corrado L., Ferrucci L., Harms M.B., Goldstein D.B., Shneider N.A., Goutman S.A., Simmons Z., Miller T.M., Chandran S., Pal S., Manousakis G., Appel S.H., Simpson E., Wang L., Baloh R.H., Gibson S.B., Bedlack R., Lacomis D., Sareen D., Sherman A., Bruijn L., Penny M., Moreno C.D.A.M., Kamalakaran S., Allen A.S., Boone B.E., Brown R.H., Carulli J.P., Chesi A., Chung W.K., Cirulli E.T., Cooper G.M., Couthouis J., Day-Williams A.G., Dion P.A., Gitler A.D., Glass J.D., Han Y., Harris T., Hayes S.D., Jones A.L., Keebler J., Krueger B.J., Lasseigne B.N., Levy S.E., Lu Y.-F., Maniatis T., McKenna-Yasek D., Myers R.M., Petrovski S., Pulst S.M., Raphael A.R., Ravits J.M., Ren Z., Rouleau G.A., Sapp P.C., Sims K.B., Staropoli J.F., Waite L.L., Wang Q., Wimbish J.R., Xin W.W., Phatnani H., Kwan J., Broach J., Arcila-Londono X., Lee E.B., Van Deerlin V.M., Fraenkel E., Ostrow L.W., Baas F., Zaitlen N., Berry J.D., Malaspina A., Fratta P., Cox G.A., Thompson L.M., Finkbeiner S., Dardiotis E., Hornstein E., MacGowan D.J.L., Heiman-Patterson T., Hammell M.G., Patsopoulos N.A., Dubnau J., Nath A., Musunuri R.L., Evani U.S., Abhyankar A., Zody M.C., Kaye J., Wyman S.K., LeNail A., Lima L., Rothstein J.D., Svendsen C.N., Van Eyk J.E., Maragakis N.J., Kolb S.J., Cudkowicz M., Baxi E., Benatar M., Taylor J.P., Wu G., Rampersaud E., Wuu J., Rademakers R., Zuchner S., Schule R., McCauley J., Hussain S., Cooley A., Wallace M., Clayman C., Barohn R., Statland J., Swenson A., Jackson C., Trivedi J., Khan S., Katz J., Jenkins L., Burns T., Gwathmey K., Caress J., McMillan C., Elman L., Pioro E.P., Heckmann J., So Y., Walk D., Maiser S., Zhang J., Silani V., Gellera C., Ratti A., Taroni F., Lauria G., Verde F., Fogh I., Tiloca C., Comi G.P., Soraru G., Cereda C., De Marchi F., Corti S., Ceroni M., Siciliano G., Filosto M., Inghilleri M., Peverelli S., Colombrita C., Poletti B., Maderna L., Del Bo R., Gagliardi S., Querin G., Bertolin C., Pensato V., Castellotti B., Camu W., Mouzat K., Lumbroso S., Corcia P., Meininger V., Besson G., Lagrange E., Clavelou P., Guy N., Couratier P., Vourch P., Danel V., Bernard E., Lemasson G., Laaksovirta H., Myllykangas L., Jansson L., Valori M., Ealing J., Hamdalla H., Rollinson S., Pickering-Brown S., Orrell R.W., Sidle K.C., Hardy J., Singleton A.B., Johnson J.O., Arepalli S., Polak M., Asress S., Al-Sarraj S., King A., Troakes C., Vance C., de Belleroche J., ten Asbroek A.L.M.A., Munoz-Blanco J.L., Hernandez D.G., Ding J., Gibbs J.R., Scholz S.W., Floeter M.K., Campbell R.H., Landi F., Bowser R., Kirby J., Pamphlett R., Gerhard G., Dunckley T.L., Brady C.B., Kowall N.W., Troncoso J.C., Le Ber I., Heiman-Patterson T.D., Kamel F., Van Den Bosch L., Strom T.M., Meitinger T., Shatunov A., Van Eijk K.R., de Carvalho M., Kooyman M., Middelkoop B., Moisse M., McLaughlin R.L., Van Es M.A., Weber M., Boylan K.B., Van Blitterswijk M., Morrison K.E., Basak A.N., Mora J.S., Drory V.E., Shaw P.J., Turner M.R., Talbot K., Hardiman O., Williams K.L., Fifita J.A., Nicholson G.A., Blair I.P., Esteban-Perez J., Garcia-Redondo A., Al-Chalabi A., Al Kheifat A., Andersen P.M., Chio A., Cooper-Knock J., Dekker A., Redondo A.G., Gotkine M., Hide W., Iacoangeli A., Kiernan M., Landers J.E., Mill J., Neto M.M., Pardina J.M., Newhouse S., Pinto S., Pulit S., Robberecht W., Shaw C., Sproviero W., Tazelaar G., Van Damme P., van den Berg L.H., van Vugt J., Veldink J.H., Zatz M., Bauer D.C., Twine N.A., Rogaeva E., Zinman L., Brice A., Feldman E.L., Ludolph A.C., Weishaupt J.H., Trojanowski J.Q., Stone D.J., Tienari P., Shaw C.E., Traynor B.J., ITALSGEN Consortium, Genomic Translation ALS Care GTAC, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Fdn, Clinical Res ALS Related Disorders, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consor, Medical Research Council (MRC), ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Università cattolica del Sacro Cuore [Roma] (Unicatt), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Lunar and Planetary Laboratory [Tucson] (LPL), University of Arizona, Università degli studi di Torino (UNITO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), New York Genome Center [New York], New York Genome Center, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), St Jude Children's Research Hospital, Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University College of London [London] (UCL), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), King‘s College London, University of New Haven [Connecticut], Princeton University, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), University Medical Center [Utrecht], Deutsches Forschungszentrum für Künstliche Intelligenz GmbH = German Research Center for Artificial Intelligence (DFKI), Mayo Clinic [Jacksonville], Trinity College Dublin, Maurice Wohl Clinical Neuroscience Institut, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Repositório da Universidade de Lisboa, Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke J F A, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Null, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Logullo, Fo, Murru, Mr, Marrosu, Mg, Conforti, Fl, Pinter, Gl, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Parish, Ld, Cau, Tb, Moreno, Cristiane de Araujo Martin, Kamalakaran, Sitharthan, Goldstein, David B, Gitler, Aaron D, Harris, Tim, Myers, Richard M, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, Lenail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W, Sidle, Katie C, Malaspina, Andrea, Hardy, John, Singleton, Andrew B, Johnson, Janel O, Arepalli, Sampath, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, Ten Asbroek, Anneloor L M A, Muñoz-Blanco, José Lui, Hernandez, Dena G, Ding, Jinhui, Gibbs, J Raphael, Scholz, Sonja W, Floeter, Mary Kay, Campbell, Roy H, Landi, Francesco, Bowser, Robert, Pulst, Stefan M, Ravits, John M, Macgowan, Daniel J L, Kirby, Janine, Pioro, Erik P, Pamphlett, Roger, Broach, Jame, Gerhard, Glenn, Dunckley, Travis L, Brady, Christopher B, Kowall, Neil W, Troncoso, Juan C, Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D, Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H, Strom, Tim M, Meitinger, Thoma, Shatunov, Aleksey, Van Eijk, Kristel R, de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Ba, Moisse, Matthieu, Mclaughlin, Russell L, Van Es, Michael A, Weber, Marku, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E, Basak, A Nazli, Mora, Jesús S, Drory, Vivian E, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Hardiman, Orla, Williams, Kelly L, Fifita, Jennifer A, Nicholson, Garth A, Blair, Ian P, Rouleau, Guy A, Esteban-Pérez, Jesú, García-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W, Maragakis, Nicholas J, Rothstein, Jeffrey D, Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexi, Goutman, Stephen A, Feldman, Eva L, Gibson, Summer B, Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Camu, William, Trojanowski, John Q, Van Deerlin, Vivianna M, Brown, Robert H, van den Berg, Leonard H, Veldink, Jan H, Harms, Matthew B, Glass, Jonathan D, Stone, David J, Tienari, Pentti, Silani, Vincenzo, Chiò, Adriano, Shaw, Christopher E, Traynor, Bryan J, Landers, John E, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Male, Als gene, Genome-wide association study, FAMILIAL ALS, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, 0302 clinical medicine, 80 and over, Psychology, Aetiology, Aged, 80 and over, 0303 health sciences, French ALS Consortium, Kinesin, KINESIN HEAVY-CHAIN, Cognitive Sciences, Human, Hereditary spastic paraplegia, Neuroscience(all), Single-nucleotide polymorphism, TARGETED DISRUPTION, Article, 03 medical and health sciences, Genetics, Humans, Amino Acid Sequence, Loss function, Aged, HEXANUCLEOTIDE REPEAT, Neuroscience (all), MUTATIONS, Amyotrophic Lateral Sclerosis, 3112 Neurosciences, 1702 Cognitive Science, medicine.disease, ITALSGEN Consortium, Answer ALS Foundation, 030104 developmental biology, ALS Sequencing Consortium, Human medicine, 1109 Neurosciences, 030217 neurology & neurosurgery, 0301 basic medicine, [SDV]Life Sciences [q-bio], Kinesins, Neurodegenerative, Genetic analysis, Genome, AMYOTROPHIC-LATERAL-SCLEROSIS, 3124 Neurology and psychiatry, Cohort Studies, Pathogenesis, Loss of Function Mutation, Missense mutation, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, NYGC ALS Consortium, General Neuroscience, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, Middle Aged, Phenotype, Settore MED/26 - NEUROLOGIA, Neurological, Project MinE ALS Sequencing Consortium, Female, Adult, Biology, GENOTYPE IMPUTATION, Genome-Wide Association Study, Young Adult, NO, Rare Diseases, medicine, SLAGEN Consortium, Gene, 030304 developmental biology, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Neurology & Neurosurgery, Human Genome, Neurosciences, AXONAL-TRANSPORT, Brain Disorders, Family member, DNA-DAMAGE, MOTOR-NEURONS, 3111 Biomedicine, Cohort Studie, Genomic Translation for ALS Care (GTAC) Consortium, Amyotrophic Lateral Sclerosi
Abstract

© 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Published
2018
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40. Total Life Cleanse : A 28-Day Program to Detoxify and Nourish the Body, Mind, and Soul

Author

Jonathan Glass and Jonathan Glass

Subjects
Mind and body, Nutrition, Detoxification (Health)
Abstract

A comprehensive guide to the integrated detox of body, mind, and spirit • Presents a practical 28-day plant-based program, divided into four cycles, to initiate and maximize physical, mental, and spiritual detoxification • Integrates the ancient wisdom of yoga, Ayurveda, and Traditional Chinese Medicine with naturopathic principles and contemporary nutritional science • Provides plant-based smoothie and meal recipes, tips on liver health and healthy elimination, exercise and yoga practices, breathing and meditation techniques to address toxic thought patterns, and Karma/Forgiveness cleansing rituals Integrating the ancient wisdom of yoga, Ayurveda, and Traditional Chinese Medicine with naturopathic principles and contemporary nutritional science, Jonathan Glass, M.Ac., C.A.T., presents a practical 28-day program, divided into four cycles, designed to initiate and maximize detoxification of your body, mind, and spirit from the harmful effects of the modern lifestyle. Glass reveals the interconnectedness of what we consume, both mentally and nutritionally, emphasizing that cleansing of the body alone will offer only a temporary solution if we do not also apply the same cleansing principles to our thoughts and actions. He provides delicious plant-based smoothie and meal recipes, step-by-step instructions to resolve blockages and stagnation in the physical or emotional body, including tips on liver health and healthy elimination, guidance on how to cleanse the proliferation of toxic thought patterns in the mind, as well as outlining a supportive Karma/Forgiveness cleanse ritual to detoxify the spirit. He explains how the soul is encased in five coverings, known as Koshas, and details how to harmonize all five Koshas through a plant-based diet, exercise, yoga, breathing techniques, and meditation/introspective practices. Citing wisdom from teachers he has revered over the years and sages past and present, as well as teachings from the Vedas and other ancient texts, Glass reinforces that how we eat, think, and live directly impacts our health in body, mind, spirit, and our relationships. He also shows how the principles of the Total Life Cleanse inherently support the environment. By empowering you with a new way of thinking, seeing, and being, the Total Life Cleanse program allows you not only to heal yourself by changing your life patterns but also to heal others, as we foster a deeper connection to the life that surrounds us and ultimately the universe.

Published
2018

41. Do stones still kill? An analysis of death from stone disease 1999-2013 in England and Wales

Author

Jonathan Glass, Wasim Mahmalji, Francesca Kum, K. Thomas, Jemma Hale, and Matthew Bultitude

Subjects
Male, Pediatrics, medicine.medical_specialty, Time Factors, Urology, Urinary system, 030232 urology & nephrology, Context (language use), 03 medical and health sciences, 0302 clinical medicine, Ureter, Epidemiology, medicine, Humans, Mortality, Stone disease, Cause of death, Wales, business.industry, Incidence (epidemiology), Surgery, Urethra, medicine.anatomical_structure, England, 030220 oncology & carcinogenesis, Female, Urinary Calculi, business
Abstract

OBJECTIVES To analyse the trends in the number of deaths attributable to urolithiasis in England and Wales over the past 15 years (1999-2013). Urolithiasis has an estimated lifetime risk of 12% in males and 6% in females and is not perceived as a life-threatening pathology. Admissions with urinary calculi contribute to 0.5% of all inpatient hospital stays, and the number of deaths attributable to stone disease has yet to be identified and presented. MATERIALS AND METHODS Office of National Statistics data relating to causes of death from urolithiasis, coded as International Classification of Diseases (ICD)-10 N20-N23, was collated and analysed for the 15-year period from 1999 to 2013 in England and Wales. These data were sub-categorised into anatomical location of calculi, age, and gender. RESULTS In all, 1954 deaths were attributed to urolithiasis from 1999 to 2013 (mean 130.3 deaths/year). Of which, 141 were attributed to ureteric stones (mean 9.4 deaths/year). Calculi of the kidney and ureter accounted for 91% of all deaths secondary to urolithiasis; lower urinary tract (bladder or urethra) calculi contributed to only 7.9% of deaths. The data revealed an overall increasing trend in mortality from urolithiasis over this 15-year period, with an increase of 3.8 deaths/year based on a linear trend (R(2) = 0.65). Overall, the number of deaths in females was significantly higher than in males (ratio 1.5:1, P < 0.001); kidney and ureteric calculi causing death had a female preponderance (1.7:1, female:male); whereas calculi of the lower urinary tract was more common in males (1:2.2, female:male). CONCLUSIONS Stone disease still causes death in the 21st century in England and Wales. This trend of increasing deaths must be placed in the context of the concurrent rising incidence of urolithiasis in the UK and the number of stone-related hospital episodes. The primary cause of death relating to complications of stone disease for each individual case should be further investigated to facilitate prevention of complications of urolithiasis.

Published
2016
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42. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study

Author

David J. Irwin, Nilufer Ertekin-Taner, Sara Rollinson, Mads Kjolby, John Hardy, Julia Kofler, Robert A. Rissman, Bernardino Ghetti, Stuart Pickering-Brown, Jonathan Glass, Carlos Cruchaga, Jonathan D. Rohrer, Keith A. Josephs, Maura Gallo, Parastoo Momeni, Emilia J. Sitek, Matthis Synofzik, Sandro Sorbi, Carlo Wilke, Oscar L. Lopez, Nigel J. Cairns, Miren Zulaica, Peter Heutink, Leonard Petrucelli, Bret M. Evers, Luisa Benussi, Jeroen van Rooij, Olivier Piguet, Sandra E. Black, Bradley F. Boeve, Cyril Pottier, Eric M. Reiman, Melissa E. Murray, Ralph B. Perkerson, Daniela Galimberti, Thomas G. Beach, Giorgio G. Fumagalli, Giacomina Rossi, David M. A. Mann, John B.J. Kwok, Harro Seelaar, Edward B. Lee, Jean-Paul Vonsattel, Didier Hannequin, Rosa Rademakers, John R. Hodges, Nicole A. Finch, John Q. Trojanowski, David S. Knopman, Yingxue Ren, Albert Lladó, Anders Nykjaer, Claire Troakes, Linn Öijerstedt, EunRan Suh, Isabelle Le Ber, Juliane Winkelmann, Ian R. Mackenzie, Glenda M. Halliday, William W. Seeley, Salvatore Spina, Simon Mead, Elio Scarpini, Fabrizio Tagliavini, Bruce L. Miller, Mariely DeJesus-Hernandez, Dennis W. Dickson, Elizabeth Christopher, Mario Masellis, Florence Pasquier, Roberta Ghidoni, Janine Diehl-Schmid, Silvia Bagnoli, Barbara Borroni, Adam L. Boxer, Adrian L. Oblak, Elizabeth Finger, Carol F. Lippa, Giuliano Binetti, Eileen H. Bigio, Vivianna M. Van Deerlin, Anna Karydas, William S. Brooks, Julie S. Snowden, Anna Richardson, Lea T. Grinberg, Manuela Neumann, Jordan Grafman, Zbigniew K. Wszolek, Edward D. Huey, Caroline Graff, John C. van Swieten, Sandra Weintraub, Raffaele Maletta, Ekaterina Rogaeva, Fermin Moreno, Raffaele Ferrari, Charles L. White, Adolfo López de Munain, Neill R. Graff-Radford, Camilla Ferrari, Jill R. Murell, Marwan N. Sabbagh, Raquel Sánchez-Valle, Marka van Blitterswijk, Alessandro Padovani, Peter Johannsen, Daniel J. Serie, Francesca Frangipane, Safa Al-Sarraj, Anna Antonell, Kevin F. Bieniek, Tsz H. Wong, Ging-Yuek Robin Hsiung, Jarosław Sławek, Matthew B. Baker, Gregory D. Jenkins, Ronald C. Petersen, Murray Grossman, Benedetta Nacmias, Tammee M. Parsons, Lawrence S. Honig, Maria Anfossi, Richard J. Caselli, Changiz Geula, Marla Gearing, M.-Marsel Mesulam, Xiaolai Zhou, Joanna M. Biernacka, Joseph E. Parisi, Irene Piaceri, Jorgen E. Nielsen, Amalia C. Bruni, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Erasmus MC other, and Neurology

Subjects
0301 basic medicine, Oncology, Male, RNA, Messenger/metabolism, Genome-wide association study, Disease, Gene mutation, genetics [Progranulins], 0302 clinical medicine, Progranulins, Cerebellum, GFRA2 protein, human, Medicine, Age of Onset, genetics [Genetic Predisposition to Disease], Genetic Predisposition to Disease/genetics, Frontotemporal lobar degeneration, metabolism [Cerebellum], Middle Aged, 3. Good health, Frontotemporal Dementia, Female, genetics [Frontotemporal Lobar Degeneration], Frontotemporal dementia, medicine.medical_specialty, Glial Cell Line-Derived Neurotrophic Factor Receptors, Mutation/genetics, Genetic counseling, genetics [Mutation], Progranulins/genetics, metabolism [RNA, Messenger], Article, 03 medical and health sciences, Internal medicine, Humans, Genetic Predisposition to Disease, ddc:610, RNA, Messenger, Cerebellum/metabolism, Aged, business.industry, metabolism [Progranulins], Case-control study, genetics [Glial Cell Line-Derived Neurotrophic Factor Receptors], Odds ratio, medicine.disease, metabolism [Frontotemporal Lobar Degeneration], metabolism [Glial Cell Line-Derived Neurotrophic Factor Receptors], 030104 developmental biology, Case-Control Studies, Mutation, GRN protein, human, Frontotemporal Lobar Degeneration/genetics, Neurology (clinical), Human medicine, Frontotemporal Lobar Degeneration, business, Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.

Published
2018
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45. Knowing our patients: it’s all in the detail

Author

Jonathan Glass

Subjects
03 medical and health sciences, 0302 clinical medicine, Psychoanalysis, Philosophy, 030212 general & internal medicine, General Medicine, 030204 cardiovascular system & hematology, Front (military)
Abstract

Finding out who’s in front of you, not what pathology you are encountering, makes all the difference, writes Jonathan Glass

Published
2019
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46. Percutaneous nephrolithotomy in England: practice and outcomes described in the Hospital Episode Statistics database

Author

Jonathan Glass, Jan van der Meulen, David A Cromwell, John Withington, Stuart Irving, William Finch, James N. Armitage, and Neil Burgess

Subjects
Hospital readmission, Database, Urinary retention, business.industry, Urology, medicine.medical_treatment, Urinary system, Outcome measures, medicine.disease, National health service, computer.software_genre, Sepsis, Statistics, medicine, medicine.symptom, Percutaneous nephrolithotomy, business, computer
Abstract

Objective To investigate the postoperative outcomes of percutaneous nephrolithotomy (PCNL) in English National Health Service (NHS) hospitals. Patients and Methods We extracted records from the Hospital Episode Statistics (HES) database for all patients undergoing PCNL between March 2006 and January 2011 in English NHS hospitals. Outcome measures were haemorrhage, infection within the index admission, and rates of emergency readmission and in-hospital mortality within 30 days of surgery. Results A total of 5750 index PCNL procedures were performed in 165 hospitals. During the index admission, haemorrhage was recorded in 81 patients (1.4%), 192 patients (3.8%) had a urinary tract infection (UTI), 95 patients (1.7%) had fever, and 41 patients (0.7%) had sepsis. There were 595 emergency readmissions in 518 patients (9.0%). Reasons for readmission were varied: 70 (1.2%) with UTI, 15 (0.3%) sepsis, 73 (1.3%) haematuria, 25 (0.4%) haemorrhage, and 25 (0.4%) acute urinary retention. There were 13 (0.2%) in-hospital deaths within 30 days of surgery. Conclusions Haemorrhage and infection represent relatively common and potentially severe complications of PCNL. Mortality is extremely rare after PCNL (about one in 400 procedures overall) but almost one in 10 patients have an unplanned hospital readmission within 30 days of surgery. Complications of PCNL may be under-reported in the HES database and need to be corroborated using other data sources.

Published
2013
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48. PD18-04 PCNL ACCESS BY UROLOGIST OR RADIOLOGIST: AN ANALYSIS OF THE BAUS PCNL REGISTRY

Author

William Finch, Stuart Irving, Jonathan Glass, Oliver Wiseman, James N. Armitage, Sarah Fowler, Neil Burgess, and John Withington

Subjects
medicine.medical_specialty, Exact test, Percutaneous, business.industry, Urology, Stone free, medicine, Radiology, Collection system, business
Abstract

INTRODUCTION AND OBJECTIVES: Obtaining percutaneous access to the collecting system of the kidney is fundamental to safe and effective PCNL. Practice varies between countries, hospitals and individual surgeons as to whether access is obtained by a urologist or an interventional radiologist (IR). The objective of this study was to compare outcomes of urologist versus IR tracts using data from the BAUS PCNL data registry. METHODS: Data submitted to the BAUS PCNL data registry between 2009 and 2015 were analysed according to whether access was obtained by a urologist or an IR. We evaluated access success, number and type of tracts, perceived and actual access difficulty, as well as outcomes including stone free rate, length of stay and complications including transfusion rates. Stone complexity was assessed using the Guy’s Stone Score. Two-tailed Fisher’s exact test was used to assess differences between the groups. RESULTS: Overall, percutaneous renal access was undertaken by an IR in 3,453 of 5,211 procedures (66.3%); this rate appeared stable over the entire study period, for all categories of stone complexity and in cases where there was predicted or actual difficulty with access. Only 1% of procedures were abandoned because of failed access and this rate was identical in each group (see Table). IRs did more multiple tracts than urologists (6.8% vs 5.1%, p1⁄40.02) but did similar rates of supracostal punctures (8.2% vs 9.2%, p1⁄40.23). Ultrasound was used more commonly by IRs than urologists (56.6% vs 21.7%, p1⁄40.0001) to guide access. There were no significant differences in complication rates, lengths of stay or stone free rates on Day 1 post-operative imaging. CONCLUSIONS: In the UK most access for PCNL is obtained by an interventional radiologist. There do not appear to be any differences in outcomes of PCNL according to whether access is obtained by a urologist or an interventional radiologist. Our findings suggest that favourable PCNL outcomes may be expected where access is obtained by individuals who have been appropriately trained and who are skilled and proficient in the procedure. However, we believe that a multidisciplinary approach to the management of patients with complex stones may lead to better outcomes.

Published
2016
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50. MP20-05 DEVELOPMENT OF THE SIMULATE URETERORENOSCOPY TRAINING CURRICULUM

Author

Muhammad Shamim Khan, Kamran Ahmed, Craig McIlhenny, Nicholas J. Rukin, Abdullatif Aydin, Prokar Dasgupta, Jonathan Glass, Matthew Bultitude, Ahmed Ma A. Shafi, James Brewin, Jake Patterson, and John E McCabe

Subjects
Training curriculum, 03 medical and health sciences, Medical education, 0302 clinical medicine, business.industry, Urology, 030232 urology & nephrology, Medicine, business
Published
2016
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