In-depth critical analysis of complications following robot-assisted radical cystectomy with intracorporeal urinary diversion

Background: Robot-assisted radical cystectomy with intracorporeal urinary diversion (iRARC) is an attractive option to open cystectomy, but the benefit in terms of improved outcomes is not established. Objective: To evaluate the early postoperative morbidity and mortality of patients undergoing iRARC and conduct a critical analysis of complications using standardised reporting criteria as stratified according to urinary diversion. Design, setting, and participants: A total of 134 patients underwent iRARC for bladder cancer at a single centre between June 2011 and July 2015. Intervention: Radical cystectomy with iRARC. Outcome measurements and statistical analysis: Patient demographics, pathologic data, and 90-d perioperative mortality and complications were recorded. Complications were reported according to the Clavien-Dindo (CD) classification and stratified according to urinary diversion type and either surgical or medical complications. The chi-square test and t test were used for categorical and continuous variables respectively. Multivariable logistic regression was performed on variables with significance in univariate analysis. Results and limitations: The 90-d all complication rate following ileal conduit and continent diversion was 68% and 82.4%, and major complications were 21.0% and 20.6% respectively. The 90-d mortality was 3% and 2.9% for ileal conduit and continent diversion patients, respectively. On multivariate analysis, the blood transfusion requirement was independently associated with major complications (p = 0.002) and all 30-d (p = 0.002) and 90-d (p = 0.012) major complications. Male patients were associated with 90-d major complications (p = 0.015). Critical analysis identified that surgical complications were responsible for 39.4% of all 90-d major complications. The incidence of surgical complications did not decline with increasing number of iRARC cases performed (p = 0.742, r = 0.31). Limitations of this study include its retrospective nature, limited sample size, and limited multivariate analysis due to the low number of major complications events. Conclusions: Although complications following iRARC are common, most are low grade. A critical analysis identified surgical complications as a cause of major complications. Addressing this issue could have a significant impact on lowering the morbidity associated with iRARC. Patient summary: We looked at the surgical outcomes in bladder cancer patients treated with minimally invasive robotic surgery. We found that surgical complications account for most major complications and previous surgical experience may be a confounding factor when interpreting results from a different centre even in a randomised trial setting

A study for an urban housing type

Thesis (M.Arch)--Massachusetts Institute of Technology, Dept. of Architecture, 1961.Accompanying drawings held by MIT Museum.Includes bibliographical references (leaves 85-87).by John Preston Shaw.M.Arc

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

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

A cricket Gene Index: a genomic resource for studying neurobiology, speciation, and molecular evolution

<p>Abstract</p> <p>Background</p> <p>As the developmental costs of genomic tools decline, genomic approaches to non-model systems are becoming more feasible. Many of these systems may lack advanced genetic tools but are extremely valuable models in other biological fields. Here we report the development of expressed sequence tags (EST's) in an orthopteroid insect, a model for the study of neurobiology, speciation, and evolution.</p> <p>Results</p> <p>We report the sequencing of 14,502 EST's from clones derived from a nerve cord cDNA library, and the subsequent construction of a Gene Index from these sequences, from the Hawaiian trigonidiine cricket <it>Laupala kohalensis</it>. The Gene Index contains 8607 unique sequences comprised of 2575 tentative consensus (TC) sequences and 6032 singletons. For each of the unique sequences, an attempt was made to assign a provisional annotation and to categorize its function using a Gene Ontology-based classification through a sequence-based comparison to known proteins. In addition, a set of unique 70 base pair oligomers that can be used for DNA microarrays was developed. All Gene Index information is posted at the DFCI Gene Indices web page</p> <p>Conclusion</p> <p>Orthopterans are models used to understand the neurophysiological basis of complex motor patterns such as flight and stridulation. The sequences presented in the cricket Gene Index will provide neurophysiologists with many genetic tools that have been largely absent in this field. The cricket Gene Index is one of only two gene indices to be developed in an evolutionary model system. Species within the genus <it>Laupala </it>have speciated recently, rapidly, and extensively. Therefore, the genes identified in the cricket Gene Index can be used to study the genomics of speciation. Furthermore, this gene index represents a significant EST resources for basal insects. As such, this resource is a valuable comparative tool for the understanding of invertebrate molecular evolution. The sequences presented here will provide much needed genomic resources for three distinct but overlapping fields of inquiry: neurobiology, speciation, and molecular evolution.</p

Dynamics of cadmium acclimation in Daphnia pulex:linking fitness costs, cross-tolerance, and hyper-induction of metallothionein

Acclimation increases tolerance to stress in individuals but is assumed to contribute fitness costs when the stressor is absent, though data supporting this widely held claim are sparse. Therefore, using clonal (i.e., genetically identical) cultures of Daphnia pulex, we isolated the contributions of acclimation to the regulation of the metal response gene, metallothionein 1 (MT1), and defined the reproductive benefits and costs of cadmium (Cd)-acclimation. Daphnia pulex were exposed for 50 parthenogenetic generations to environmentally realistic levels (1 μg Cd/L), and tolerance to Cd and other metals assessed during this period via standard toxicity tests. These tests revealed (1) increased tolerance to Cd compared to genetically identical nonacclimated cultures, (2) fitness costs in Cd-acclimated Daphnia when Cd was removed, and (3) cross-tolerance of Cd-acclimated Daphnia to zinc and silver, but not arsenic, thereby defining a functional role for metallothionein. Indeed, Cd-acclimated clones had significantly higher expression of MT1 mRNA than nonacclimated clones, when Cd exposed. Both the enhanced induction of MT1 and tolerant phenotype were rapidly lost when Cd was removed (1–2 generations), which is further evidence of acclimation costs. These findings provide evidence for the widely held view that acclimation is costly and are important for investigating evolutionary principles of genetic assimilation and the survival mechanisms of natural populations that face changing environments

Observable Effects of Scalar Fields and Varying Constants

We show by using the method of matched asymptotic expansions that a sufficient condition can be derived which determines when a local experiment will detect the cosmological variation of a scalar field which is driving the spacetime variation of a supposed constant of Nature. We extend our earlier analyses of this problem by including the possibility that the local region is undergoing collapse inside a virialised structure, like a galaxy or galaxy cluster. We show by direct calculation that the sufficient condition is met to high precision in our own local region and we can therefore legitimately use local observations to place constraints upon the variation of "constants" of Nature on cosmological scales.Comment: Invited Festscrift Articl

ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function

Mutations in TANK binding kinase 1 (TBK1) have been linked to amyotrophic lateral sclerosis. Some TBK1 variants are nonsense and are predicted to cause disease through haploinsufficiency; however, many other mutations are missense with unknown functional effects. We exome sequenced 699 familial amyotrophic lateral sclerosis patients and identified 16 TBK1 novel or extremely rare protein-changing variants. We characterized a subset of these: p.G217R, p.R357X, and p.C471Y. Here, we show that the p.R357X and p.G217R both abolish the ability of TBK1 to phosphorylate 2 of its kinase targets, IRF3 and optineurin, and to undergo phosphorylation. They both inhibit binding to optineurin and the p.G217R, within the TBK1 kinase domain, reduces homodimerization, essential for TBK1 activation and function. Finally, we show that the proportion of TBK1 that is active (phosphorylated) is reduced in 5 lymphoblastoid cell lines derived from patients harboring heterozygous missense or in-frame deletion TBK1 mutations. We conclude that missense mutations in functional domains of TBK1 impair the binding and phosphorylation of its normal targets, implicating a common loss of function mechanism, analogous to truncation mutations