Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ.

CONTEXT: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken. OBJECTIVE: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. PATIENTS, DESIGN, AND SETTING: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. RESULTS: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases. CONCLUSIONS: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.This study made use of data generated by the UK10K Project and we acknowledge the contribution of the UK10K Consortium. This work was supported by Wellcome Trust Grants 100585/Z/12/Z (to N.S.), and 095564/Z/11/Z (to V.K.C.) and the National Institute for Health Research Cambridge Biomedical Research Center (to V.K.C., N.S.). E.G.S and C.A.A. are supported by the Wellcome Trust (098051). Funding for the UK10K Project was provided by the Wellcome Trust under award WT091310

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Arabic journals\u27 literature about Sinai : a bibliometric study

تتناول الدراسة موضوع سيناء فى الإنتاج الفكري باللغة العربية فى الدوريات العربية في الفترة من 1900 حتى 2012، وذلك للتعرف على التنوع الموضوعي والنوعي للمقالات عن سيناء، بهدف إماطة اللثام عن مناطق القوة والضعف في هذا الإنتاج للاستفادة من مواطن القوة والعمل على مناطق الضعف لتقويتها. وقد اعتمدت الدراسة على المنهج الوصفي التحليلي لملاءمته لمثل هذا النوع من الدراسات، فقد تم التجميع الوراقي للإنتاج الفكري للمقالات باللغة العربية عن سيناء وإنشاء ببليوجرافية لهذا الإنتاج، لتيسير التعامل معه، عن طريق تحليل هذا الإنتاج باستخدام أساليب القياسات الوراقية مثل: قانون برادفورد للتشتت، كما وزع هذا الإنتاج موضوعيًا ونوعيًا وزمنيًا وجغرافيًا لدراسة نموه وتطوره، وقد انتهت الدراسة إلى عدة نتائج منها أن عدد الدوريات البؤرية بلغ ست مجلات تمثل مختلف المجالات الموضوعية، مثلت السياسة التوجه الموضوعي الأساسي لنصف مجموع تلك الدوريات، وأن عقد السبعينيات يمثل الفترة الأكثر إنتاجًا من حيث عدد المقالات بأكثر من ربع الإنتاج الإجمالي.The study deals with the topic of Sinai in literature in the Arabic language in Arab journals in the period from 1900 to 2012, in order to identify the objective and qualitative diversity of articles about Sinai, with the aim of revealing the areas of strength and weakness in this production in order to benefit from the strengths and work on the areas of weakness to strengthen them. The study relied on the descriptive analytical method for its suitability to this type of study. The paper collection of the literature of articles in Arabic about Sinai was done and a bibliography of this production was created, to facilitate dealing with it, by analyzing this production using paper measurement methods such as: Bradford’s Law of Dispersion. This production was distributed objectively, qualitatively, temporally, and geographically to study its growth and development. The study concluded with several results, including that the number of focal journals reached six magazines representing various subject areas, politics represented the basic objective orientation for half of the total of these journals, and that the decade of the seventies represented the most productive period in terms of the number Articles accounted for more than a quarter of the total production

Heterotopic chondrocytes and three dimensional cocultures for in autologe joint reconstruction

Die Matrix assistierte autologe Chondrozyten Implantation (MACI) stellt den momentanen Goldstandard zur Behandlung großer Gelenkknorpeldefekte dar. Der therapeutische Erfolg wird durch hohe Entnahmemorbiditäten sowie die geringe Verfügbarkeit von gesundem Spendergewebe stark limitiert. Falls adulte heterotope Knorpelzellen ein belastbares hyalines Ersatzgewebe generieren könnten, bestünde hier eine vielversprechende Modifikations- möglichkeit der herkömmlichen MACI. Deshalb wurde in der vorliegenden Arbeit die vergleichende Charakterisierung artikulärer, aurikulärer und nasoseptaler Chondrozyten in zweidimensionalen (2D) und dreidimensionalen (3D) in vitro Kultursystemen sowie im in vivo Xenograft-Nacktmausmodell vorgenommen, um anschließend die Kompatibilität sowie die wechselseitige Beeinflussung heterotoper Chondrozyten in Ko-Kulturen (aurikulär/artikulär, nasoseptal/artikulär) zu untersuchen. Dabei wurden wichtige chondrogene Marker und extrazelluläre Matrix (EZM)-Bestandteile (Sox9, Aggrecan; Kollagene Typ I, II, IX, XI, Elastin, Lubricin, β1-Integrin) mittels RTD-PCR-, Western Blot-, immunzytochemischer und quantitativer Analysen nachgewiesen. Die Knorpelneogenese in den in vitro und in vivo 3D Kulturen wurde (immun-) histologisch dargestellt. In der 2D Kultur wurde der Hauptknorpelmarker Kollagen Typ II in artikulären Chondrozyten höher exprimiert. Auch im 3D-Alginatkultursystem lag die Expression des Kollagens Typ II über den gesamten Untersuchungszeitraum unterhalb des Niveaus in den artikulären Chondrozyten. Die PGA-assoziierten Kulturen zeigten eine hohe Vitalität und eine umfangreiche EZM-Produktion. Bezüglich der Kollagen Typ II Expression konnten keine signifikanten Unterschiede mehr zwischen den artikulären und den heterotopen Chondrozyten nachgewiesen werden. Die guten Kollagen Typ II/ I Ratios sprechen für eine erfolgreiche und mit artikulären Chondrozyten vergleichbare Redifferenzierung der heterotopen Chondrozyten in dem PGA-assoziierten Kultursystem. Im in vivo Xenograft-Nacktmausmodell konnte mit allen heterotopen Chondrozytenarten eine Bildung von hyalinartigem Knorpelgewebe erzielt werden. In den nasoseptalen Chondrozyten Kulturen wurde dabei eine stark ausgeprägte Ossifikation evident. Die Präsenz elastischer Fasern konnte jedoch in keiner Kultur nachgewiesen werden. Über eine Zell-Markierung wurde die Koexistenz der verschiedenen Chondrozytenarten 2D sowie 3D Ko-Kulturen bewiesen. Die in den PGA- assoziierten Ko- Kulturen im Vergleich zu den artikulären Mono-Kulturen günstigere Kollagen Typ II/ I Ratio deutet auf eine positive Wechselwirkung der heterotopen Chondrozyten hin. Die dieser Arbeit zu Grunde liegenden Daten sprechen für die weitere Verwendung heterotoper Chondrozyten, im Besonderen aurikulärer Chondrozyten, in einem experimentellen Kontext der MACI.The Matrix assisted autolouge chondrocyte implantation (MACI) is today's gold standard for the treatment of huge articular cartilage defects. The therapeutically outcome is strongly limited by a high donor site morbidity and the small amount of available healthy articular cartilage tissue. It would be a promising approach for the common MACI, if adult heterotopic chondrocytes are able to build up a resistible hyaline replacement tissue. That`s why a major part in the present work was a comparative characterisation of articular, auricular and nasoseptal chondrocytes in two dimensional (2D) and three dimensional (3D) in vitro culture systems as well as in an in vivo xenograft nude mice model. Further the capability and interaction between heterotopic chondrocytes in couture systems (auricular/articular, nasoseptal/articular) was investigated. Their fore important chondrogenic markers and extracellular matrix (ECM)-components (sox9, aggrecan, collagen type I, II , IX, XI, elastin, lubricin, β1-integrin ) was analysed by RTD- PCR, western bloting, immuncytochemical and quantitative ECM measurement. The cartilage neogenesis of in vitro and in vivo cultures was visualised via (immune-) histological technics. In the 2D cultures as well as in the 3D alginate culture system the major cartilage marker collagen type II was upmost expressed in articular chondrocytes. During the whole investigation time the PGA-Scaffold associated cultures shows high vitality and an extensive ECM- Production. Concerning the collagen type II expression no significant differences was found between the heterotopic chondrocytes. The good collagen type II / type I ratio allude to a successful redifferentiation of the heterotopic chondrocytes in the PGA-Scaffold associated culture system comparable to those of the articular ones. During the in vivo xenograft nude mice experiments a hyaline like cartilage tissue was produced by al heterotopic chondrocyte cultures. Thereby a makeable ossification was evident especially in the nasoseptal chondrocyte cultures. Further no elastic fibres could be detected in al type of cultures. Due to cell tracking technics the coexistence of both heterotopic chondrocyte types was proven in the used 2D and 3D co-culture systems. The collagen type II / type I ratio was more favourable in co-cultures than in articular mono-cultures which indicates a positive and mutual interplay of the heterotopic chondrocytes. The finding of this work together argues for further investigation of heterotopic chondrocytes, especially auricular chondrocytes, for MACI in an experimental context

dot-app

Cytoscape application for exporting/importing Graphviz files (.dot, .gv

dot-app: a Graphviz-Cytoscape conversion plug-in [version 1; referees: 1 approved, 2 approved with reservations]

dot-app is a Cytoscape 3 app that allows Cytoscape to import and export Graphviz (*.dot, *.gv) files, also known as DOT files due to the *.dot extension and their conformance to the DOT language syntax. The DOT format was originally created in the early 2000s to represent graph topologies, layouts and formatting. DOT-encoded files are produced and consumed by a number of open-source graph applications, including GraphViz, Gephi, neato, smyrna, and others. While DOT-based graph applications are popular, they emphasize general graph layout and styling over the topological and semantic analysis functions available in domain-focused applications such as Cytoscape. While domain-focused applications have easy access to large networks (10,000 to 100,000 nodes) and advanced analysis and formatting, they do not offer all of the styling options that DOT-based applications (particularly GraphViz) do. dot-app enables the interchange of networks between Cytoscape and DOT-based applications so that users can benefit from the features of both. dot-app was first deployed to the Cytoscape App Store in August 2015, has since registered more than 1,200 downloads, and has been highly rated by more than 20 users