340 research outputs found
Short-term surgical complications after radical hysterectomy - a nationwide cohort study
Introduction: Centralization has, among other aspects, been argued to have an impact on quality of care in terms of surgical morbidity. Next, monitoring quality of care is essential in identifying areas of improvement. This nationwide cohort study was conducted to determine the rate of short-term surgical complications and to evaluate its possible predictors in women with early-stage cervical cancer. Material and methods: Women diagnosed with early-stage cervical cancer, 2009 FIGO stages IB1 and IIA1, between 2015 and 2017 who underwent radical hysterectomy with pelvic lymphadenectomy in 1 of the 9 specialized medical centers in the Netherlands, were identified from the Netherlands Cancer Registry. Women were excluded if primary treatment consisted of hysterectomy without parametrial dissection or radical trachelectomy. Women in whom radical hysterectomy was aborted during the procedure, were also excluded. Occurrence of intraoperative and postoperative complications and type of complications, developing within 30Â days after surgery, were prospectively registered. Multivariable logistic regression analysis was used to identify predictors of surgical complications. Results: A total of 472 women were selected, of whom 166 (35%) developed surgical complications within 30Â days after radical hysterectomy. The most frequent complications were urinary retention with catheterization in 73 women (15%) and excessive perioperative blood loss >1000Â mL in 50 women (11%). Open surgery (odds ratio [OR] 3.42; 95% CI 1.73-6.76), chronic pulmonary disease (OR 3.14; 95% CI 1.45-6.79), vascular disease (OR 1.90; 95% CI 1.07-3.38), and medical center (OR 2.83; 95% CI 1.18-6.77) emerged as independent predictors of the occurrence of complications. Body mass index (OR 0.94; 95% CI 0.89-1.00) was found as a negative predictor of urinary retention. Open surgery (OR 36.65; 95% CI 7.10-189.12) and body mass index (OR 1.15; 95% CI 1.08-1.22) were found to be independent predictors of excessive perioperative blood loss. Conclusions: Short-term surgical complications developed in 35% of the women after radical hysterectomy for early-stage cervical cancer in the Netherlands, a nation with centralized surgical care. Comorbidities predict surgical complications, and open surgery is associated with excessive perioperative blood loss
Automating the Communication of Cybersecurity Knowledge: Multi-Case Study
Cybersecurity is essential for the protection of companies against cyber
threats. Traditionally, cybersecurity experts assess and improve a company's
capabilities. However, many small and medium-sized businesses (SMBs) consider
such services not to be affordable. We explore an alternative do-it-yourself
(DIY) approach to bringing cybersecurity to SMBs. Our method and tool, CYSEC,
implements the Self-Determination Theory (SDT) to guide and motivate SMBs to
adopt good cybersecurity practices. CYSEC uses assessment questions and
recommendations to communicate cybersecurity knowledge to the end-user SMBs and
encourage self-motivated change. In this paper, the operationalisation of SDT
in CYSEC is presented and the results of a multi-case study shown that offer
insight into how SMBs adopted cybersecurity practices with CYSEC. Effective
automated cybersecurity communication depended on the SMB's hands-on skills,
tools adaptedness, and the users' willingness to documenting confidential
information. The SMBs wanted to learn in simple, incremental steps, allowing
them to understand what they do. An SMB's motivation to improve security
depended on the fitness of assessment questions and recommendations with the
SMB's business model and IT infrastructure. The results of this study indicate
that automated counselling can help many SMBs in security adoption. The final
publication is available at Springer via
https://link.springer.com/chapter/10.1007%2F978-3-030-59291-2_8Comment: 14 pages, 1 figure, 13th World Conference on Information Security
Educatio
De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development
Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD
blaKPC and rmtB on a single plasmid in Enterobacter amnigenus and Klebsiella pneumoniae isolates from the same patient
Enterobacter amnigenus (EA76) and Klebsiella pneumoniae (KP76) isolates with multidrug-resistant (MDR) patterns were identified from the same patient in the neurosurgery department of our hospital. An outbreak of MDR K. pneumoniae had also occurred in this department. To characterize the resistance mechanism and molecular epidemiology of these isolates, sequential experiments including antimicrobial susceptibility testing, polymerase chain reaction (PCR), plasmid analysis, pulsed field gel electrophoresis (PFGE), and multilocus sequence typing (MLST) were performed. EA76 and KP76 were resistant to all of the antibiotics tested, except colistin and tigecycline. blaKPC-2, blaTEM-1, blaSHV-12, blaCTX-M-3, blaCTX-M-14, and rmtB genes were identified in both isolates, with blaKPC-2, blaTEM-1, blaCTX-M-14, and rmtB being co-carried on one plasmid in each isolate. Further analysis showed different restriction patterns between the two KPC-carrying plasmids. Of the 11 carbapenem-resistant isolates found in the outbreak, all were resistant to all of the ÎČ-lactams tested, with 63.64% (7/11) also exhibiting resistance to aminoglycosides and 72.73% (8/11) exhibiting resistance to quinolones. PCR analysis and molecular typing of the 11 K. pneumoniae strains revealed that the seven aminoglycoside-resistant isolates shared the same antibiotic-resistant gene pattern and identical or one-band-difference PFGE profiles relative to KP76. In addition, all of the eight aminoglycoside-resistant isolates, including KP76, belonged to the national epidemic clone ST11. The overall results indicate the emergence of E. amnigenus and outbreak of ST11 K. pneumoniae, with both co-harboring blaKPC and rmtB genes on a single plasmid in our neurosurgery wards
Homozygous loss-of-function variants in FILIP1 cause autosomal recessive arthrogryposis multiplex congenita with microcephaly
Arthrogryposis multiplex congenita forms a broad group of clinically and etiologically heterogeneous disorders characterized by congenital joint contractures that involve at least two different parts of the body. Neurological and muscular disorders are commonly underlying arthrogryposis. Here, we report five affected individuals from three independent families sharing an overlapping phenotype with congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly and facial dysmorphism. Using exome sequencing, we identified homozygous truncating variants in FILIP1 in all patients. FILIP1 is a regulator of filamin homeostasis required for the initiation of cortical cell migration in the developing neocortex and essential for the differentiation process of cross-striated muscle cells during myogenesis. In summary, our data indicate that bi-allelic truncating variants in FILIP1 are causative of a novel autosomal recessive disorder and expand the spectrum of genetic factors causative of arthrogryposis multiplex congenita
An RIG-I-Like RNA Helicase Mediates Antiviral RNAi Downstream of Viral siRNA Biogenesis in Caenorhabditis elegans
Dicer ribonucleases of plants and invertebrate animals including Caenorhabditis elegans recognize and process a viral RNA trigger into virus-derived small interfering RNAs (siRNAs) to guide specific viral immunity by Argonaute-dependent RNA interference (RNAi). C. elegans also encodes three Dicer-related helicase (drh) genes closely related to the RIG-I-like RNA helicase receptors which initiate broad-spectrum innate immunity against RNA viruses in mammals. Here we developed a transgenic C. elegans strain that expressed intense green fluorescence from a chromosomally integrated flock house virus replicon only after knockdown or knockout of a gene required for antiviral RNAi. Use of the reporter nematode strain in a feeding RNAi screen identified drh-1 as an essential component of the antiviral RNAi pathway. However, RNAi induced by either exogenous dsRNA or the viral replicon was enhanced in drh-2 mutant nematodes, whereas exogenous RNAi was essentially unaltered in drh-1 mutant nematodes, indicating that exogenous and antiviral RNAi pathways are genetically distinct. Genetic epistatic analysis shows that drh-1 acts downstream of virus sensing and viral siRNA biogenesis to mediate specific antiviral RNAi. Notably, we found that two members of the substantially expanded subfamily of Argonautes specific to C. elegans control parallel antiviral RNAi pathways. These findings demonstrate both conserved and unique strategies of C. elegans in antiviral defense
TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.
DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.This work was supported by funding from the Medical Research Council and the European Research Council (ERC, 281847) (A.P.J.), the Lister Institute for Preventative Medicine (A.P.J. and G.S.S.), Medical Research Scotland (L.S.B.), German Federal Ministry of Education and Research (BMBF, 01GM1404) and E-RARE network EuroMicro (B.W), Wellcome Trust (M. Hurles), CMMC (P.N.), Cancer Research UK (C17183/A13030) (G.S.S. and M.R.H), Swiss National Science Foundation (P2ZHP3_158709) (O.M.), AIRC (12710) and ERC/EU FP7 (CIG_303806) (S.S.), Cancer Research UK (C6/A11224) and ERC/EU FP7 (HEALTH-F2- 2010-259893) (A.N.B. and S.P.J.).This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.345
Mast Cell Diseases in Practice and Research: Issues and Perspectives Raised by Patients and Their Recommendations to the Scientific Community and Beyond
Background: Since 2010, patients and physicians have collaborated to understand unmet needs of patients with mast cell diseases, incorporating mastocytosis and mast cell activation disorders, which include mast cell activation syndromes. Objective: This Open Innovation in Science project aims to expand understanding of the needs of patients affected by mast cell diseases, and encourage global communication among patient advocacy groups, physicians, researchers, industry, and government. A major aim is to support the scientific community's efforts to improve diagnosis, management, therapy, and patientsâ quality of life by addressing unmet needs. Methods: In collaboration with mast cell disease specialists, 13 patient advocacy groups from 12 countries and regions developed lists of top patient needs. A core team of leaders from patient advocacy groups collected and analyzed the data and proposed possible actions to address patient needs. Results: Findings identified similarities and differences among participating countries in unmet needs between patients with mastocytosis and those with mast cell activation syndromes. Issues emphasized struggles relating to the nature and rarity of mast cell diseases, their impact on quality of life, the diagnostic process, access to appropriate care, more effective treatment, and the need for research. Conclusions: Solutions vary across countries because situations differ, in particular regarding the existence of and access to centers of excellence and reference centers. Multifaceted mast cell activation syndrome barriers necessitate innovative approaches to improve access to appropriate care. The outcomes of this project should greatly support scientists and clinicians in their efforts to improve diagnosis, management, and treatment of patients with mastocytosis and mast cell activation disorders.The authors thank Tania Bray, Jan Hempstead, Heather
Mayne, Joanne Mulder-Brambleby, and Irene Wilson for their
supporting contributions, and all patients and families affected
by MCDs, who shared their needs and concerns for development
of this project. Authors involved in study conception and design
were P. Valent, S.V. Jennings, C.C. Finnerty, J.S. Hobart, M.
MartĂn-MartĂnez, K.A. Sinclair, V.M. Slee, J. Agopian, C. Akin,
I. Ălvarez-Twose, P. Bonadonna, A.A. Bowman, K. Brockow, H.
Bumbea, C. de Haro, J.S. Fok, K. Hartmann, N. Hegmann, O.
Hermine, M. Kalisiak, C.H. Katelaris, J. Kurz, P. Marcis, D.
Mayne, D. Mendoza, A. Moussy, G. Mudretzkyj, N. Nidelea
Vaia, M. Niedoszytko, H. Oude Elberink, A. Orfao, D.H.
Radia, S. Rosenmeier, E. Ribada, W. Schinhofen, J. Schwaab, F.
Siebenhaar, M. Triggiani, G. Tripodo, R. Velazquez, Y. Wielink,
F. Wimazal, T. Yigit, and C. Zubrinich. Authors involved in acquisition and review of data were S.V. Jennings, C.C. Finnerty,
J.S. Hobart, M. MartĂn-MartĂnez, K.A. Sinclair, V.M. Slee, J.
Agopian, C. Akin, I. Ălvarez-Twose, P. Bonadonna, A.A.
Bowman, K. Brockow, H. Bumbea, C. de Haro, J.S. Fok, K.
Hartmann, N. Hegmann, O. Hermine, M. Kalisiak, C.H.
Katelaris, J. Kurz, P. Marcis, D. Mayne, D. Mendoza, A.
Moussy, G. Mudretzkyj, N. Nidelea Vaia, M. Niedoszytko, H.
Oude Elberink, A. Orfao, D.H. Radia, S. Rosenmeier, E. Ribada, W. Schinhofen, J. Schwaab, F. Siebenhaar, M. Triggiani, G.
Tripodo, R. Velazquez, Y. Wielink, F. Wimazal, T. Yigit, C.
Zubrinich, and P. Valent. The Core Group (analysis and interpretation of data and drafting of the manuscript) include S.V.
Jennings, C.C. Finnerty, J.S. Hobart, M. MartĂn-MartĂnez, K.A.
Sinclair, and V.M. Slee. Critical revision was performed by S.V.
Jennings, C.C. Finnerty, J.S. Hobart, M. MartĂn-MartĂnez, K.A.
Sinclair, V.M. Slee, J. Agopian, C. Akin, I. Ălvarez-Twose, P.
Bonadonna, A.A. Bowman, K. Brockow, H. Bumbea, C. de
Haro, J.S. Fok, K. Hartmann, N. Hegmann, O. Hermine, M.
Kalisiak, C.H. Katelaris, J. Kurz, P. Marcis, D. Mayne, D.
Mendoza, A. Moussy, G. Mudretzkyj, N. Nidelea Vaia, M.
Niedoszytko, H. Oude Elberink, A. Orfao, D.H. Radia, S.
Rosenmeier, E. Ribada, W. Schinhofen, J. Schwaab, F. Siebenhaar, M. Triggiani, G. Tripodo, R. Velazquez, Y. Wielink, F Wimazal, T. Yigit, C. Zubrinich, and P. Valent
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