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| 2. |
- Drake, Thomas M., et al.
(author)
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Outcomes following small bowel obstruction due to malignancy in the national audit of small bowel obstruction
- 2019
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In: European Journal of Surgical Oncology. - : Elsevier BV. - 0748-7983 .- 1532-2157. ; 45:12, s. 2319-2324
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Journal article (peer-reviewed)abstract
- © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology Introduction: Patients with cancer who develop small bowel obstruction are at high risk of malnutrition and morbidity following compromise of gastrointestinal tract continuity. This study aimed to characterise current management and outcomes following malignant small bowel obstruction. Methods: A prospective, multicentre cohort study of patients with small bowel obstruction who presented to UK hospitals between 16th January and 13th March 2017. Patients who presented with small bowel obstruction due to primary tumours of the intestine (excluding left-sided colonic tumours) or disseminated intra-abdominal malignancy were included. Outcomes included 30-day mortality and in-hospital complications. Cox-proportional hazards models were used to generate adjusted effects estimates, which are presented as hazard ratios (HR) alongside the corresponding 95% confidence interval (95% CI). The threshold for statistical significance was set at the level of P ≤ 0.05 a-priori. Results: 205 patients with malignant small bowel obstruction presented to emergency surgery services during the study period. Of these patients, 50 had obstruction due to right sided colon cancer, 143 due to disseminated intraabdominal malignancy, 10 had primary tumours of the small bowel and 2 patients had gastrointestinal stromal tumours. In total 100 out of 205 patients underwent a surgical intervention for obstruction. 30-day in-hospital mortality rate was 11.3% for those with primary tumours and 19.6% for those with disseminated malignancy. Severe risk of malnutrition was an independent predictor for poor mortality in this cohort (adjusted HR 16.18, 95% CI 1.86 to 140.84, p = 0.012). Patients with right-sided colon cancer had high rates of morbidity. Conclusions: Mortality rates were high in patients with disseminated malignancy and in those with right sided colon cancer. Further research should identify optimal management strategy to reduce morbidity for these patient groups.
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| 3. |
- Fresard, Laure, et al.
(author)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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In: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Journal article (peer-reviewed)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 4. |
- Hsiao, Tiger Yu-Yang, et al.
(author)
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JWST Reveals a Possible z similar to 11 Galaxy Merger in Triply Lensed MACS0647-JD
- 2023
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 949:2
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Journal article (peer-reviewed)abstract
- MACS0647-JD is a triply lensed z similar to 11 galaxy originally discovered with the Hubble Space Telescope. The three lensed images are magnified by factors of similar to 8, 5, and 2 to AB mag 25.1, 25.6, and 26.6 at 3.5 mu m. The brightest is over a magnitude brighter than other galaxies recently discovered at similar redshifts z > 10 with JWST. Here, we report new JWST imaging that clearly resolves MACS0647-JD as having two components that are either merging galaxies or stellar complexes within a single galaxy. The brighter larger component "A" is intrinsically very blue (ss similar to-2.6 +/- 0.1), likely due to very recent star formation and no dust, and is spatially extended with an effective radius similar to 70 +/- 24 pc. The smaller component "B" (r similar to 20-+ 58 pc) appears redder (ss similar to-2 +/- 0.2), likely because it is older (100-200 Myr) with mild dust extinction (AV similar to 0.1 mag). With an estimated stellar mass ratio of roughly 2:1 and physical projected separation similar to 400 pc, we may be witnessing a galaxy merger 430 million years after the Big Bang. We identify galaxies with similar colors in a high-redshift simulation, finding their star formation histories to be dissimilar, which is also suggested by the spectral energy distribution fitting, suggesting they formed further apart. We also identify a candidate companion galaxy "C" similar to 3 kpc away, likely destined to merge with A and B. Upcoming JWST Near Infrared Spectrograph observations planned for 2023 January will deliver spectroscopic redshifts and more physical properties for these tiny magnified distant galaxies observed in the early universe.
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| 5. |
- Cammareri, Patrizia, et al.
(author)
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Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma
- 2016
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Journal article (peer-reviewed)abstract
- Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF/MAPK pathway activation. Here we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFβ Smad signalling, which is localized to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through Braf V600E or Kras G12D knockin) and TGFβ signalling ablation (through Tgfbr1 deletion) in LGR5 +ve stem cells enables rapid cSCC development in the mouse. Mutation of Tp53 (which is commonly mutated in sporadic cSCC) coupled with Tgfbr1 deletion in LGR5 +ve cells also results in cSCC development. These findings indicate that LGR5 +ve stem cells may act as cells of origin for cSCC, and that RAS/RAF/MAPK pathway hyperactivation or Tp53 mutation, coupled with loss of TGFβ signalling, are driving events of skin tumorigenesis.
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| 6. |
- Gafar, Fajri, et al.
(author)
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Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents : a systematic review and individual patient data meta-analysis
- 2023
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In: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 61:3
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Research review (peer-reviewed)abstract
- Background Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.Methods We systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24 and Cmax were assessed with linear mixed-effects models.Results Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24 were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L−1), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L−1), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L−1) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L−1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0–24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24 and slow acetylators had higher isoniazid AUC0–24 than intermediate acetylators. Determinants of Cmax were generally similar to those for AUC0–24.Conclusions This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.
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| 7. |
- Orton, G, et al.
(author)
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Earth-based observations of the Galileo probe entry site
- 1996
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In: SCIENCE. - : AMER ASSOC ADVANCEMENT SCIENCE. - 0036-8075. ; 272:5263, s. 839-840
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Journal article (peer-reviewed)abstract
- Earth-based observations of Jupiter indicate that the Galileo probe probably entered Jupiter's atmosphere just inside a region that has less cloud cover and drier conditions than more than 99 percent of the rest of the planet. The visual appearance of the
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| 8. |
- Rahmati, Omid, et al.
(author)
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Capability and robustness of novel hybridized models used for drought hazard modeling in southeast Queensland, Australia
- 2020
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In: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 718
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Journal article (peer-reviewed)abstract
- Widespread detrimental and long-lasting droughts are having catastrophic impacts around the globe. Researchers, organizations, and policy makers need to work together to obtain precise information, enabling timely and accurate decision making to mitigate drought impacts. In this study, a spatial modeling approach based on an adaptive neuro-fuzzy inference system (ANFIS) and several metaheuristic optimizations (ANFIS-BA, ANFIS-GA, ANFIS-ICA, ANFIS-PSO) was developed to predict the spatial occurrence of drought in a region in southeastern Queensland, Australia. In this approach, data describing the distribution of eight drought-contributing factors were prepared for input into the models to serve as independent variables. Relative departures of rainfall (RDR) and relative departures of soil moisture (RDSM) were analyzed to identify locations where drought conditions have occurred. The set of locations in the study area identified as having experienced drought conditions was randomly divided into two groups, 70% were used for training and 30% for validation. The models employed these data to generate maps that predict the locations that would be expected to experience drought. The prediction accuracy of the model-produced drought maps was scrutinized with two evaluation metrics: area under the receiver operating characteristic curve (AUC) and root mean square error (RMSE). The results demonstrate that the hybridized models (ANFIS-BA (AUC(mean) = 83.7%, RMSEmean = 0.236), ANFIS-GA (AUC(mean) = 81.62%, RMSEmean = 0.247), ANFIS-ICA (AUC(mean) = 82.12%, RMSEmean = 0.247), and ANFIS-PSO (AUC(mean) = 81.42%, RMSEmean = 0.255)) yield better predictive performance than the standalone ANFIS model (AUC(mean) = 71.8%, RMSEmean = 0.344). Furthermore, sensitivity analyses indicated that plantavailable water capacity, the percentage of soil comprised of sand, and mean annual precipitation were the most important predictors of drought hazard. The versatility of the new approach for spatial drought modeling and the capacity of ANFIS model hybridization to improve model performance suggests great potential to assist decision makers in their formulations of drought risk, recovery, and response management, and in the development of contingency plans.
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| 9. |
- Sjoberg Bexelius, T, et al.
(author)
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Hyperthermic intraperitoneal chemotherapy (HIPEC) as another treatment modality for desmoplastic round cell tumour patients: first paediatric experience from UK
- 2021
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In: BMJ case reports. - : BMJ. - 1757-790X. ; 14:1
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Journal article (peer-reviewed)abstract
- We present the first young paediatric patient with desmoplastic small round cell tumour (DSRCT) treated in UK with hyperthermic intraperitoneal chemotherapy (HIPEC). A 7-year-old girl was diagnosed with abdominal DSRCT with peritoneal and liver metastases. After six cycles of chemotherapy she obtained a partial response, including almost complete resolution of the two liver metastases. It was decided to pursue cytoreductive surgery (CRS) combined with HIPEC, a procedure commonly performed in adults, but seldom in a child. The surgery was macroscopically complete and the HIPEC uncomplicated. She continued treatment without delays, including whole abdomino-pelvic radiotherapy and maintenance chemotherapy (cyclophosphamide/vinorelbine for 12 months). She is currently in complete remission 4 months after end of treatment and 26 months after diagnosis. HIPEC was made possible by successful collaboration between multiple teams. CRS-HIPEC proved to be safe and feasible and could be offered to other children with diagnoses of peritoneal malignancies across the UK.
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| 10. |
- Vanzella, Eros, et al.
(author)
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JWST/NIRCam Probes Young Star Clusters in the Reionization Era Sunrise Arc
- 2023
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 945:1
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Journal article (peer-reviewed)abstract
- Star cluster formation in the early universe and its contribution to reionization remains largely unconstrained to date. Here we present JWST/NIRCam imaging of the most highly magnified galaxy known at z ∼ 6, the Sunrise arc. We identify six young massive star clusters (YMCs) with measured radii spanning from ∼20 down to ∼1 pc (corrected for lensing magnification), estimated stellar masses of ∼106–7 M⊙, and ages of 1–30 Myr based on SED fitting to photometry measured in eight filters extending to rest frame 7000 Å. The resulting stellar mass surface densities are higher than 1000 M⊙ pc−2 (up to a few 105 M⊙ pc−2), and their inferred dynamical ages qualify the majority of these systems as gravitationally bound stellar clusters. The star cluster ages map the progression of star formation along the arc, with two evolved systems (≳10 Myr old) followed by very young clusters. The youngest stellar clusters (<5 Myr) show evidence of prominent Hβ+[O ııı] emission based on photometry with equivalent widths larger than >1000 Å rest frame and are hosted in a 200 pc sized star-forming complex. Such a region dominates the ionizing photon production with a high efficiency log(ξion [Hz erg-1]~25.7 . A significant fraction of the recently formed stellar mass of the galaxy (10%–30%) occurred in these YMCs. We speculate that such sources of ionizing radiation boost the ionizing photon production efficiency, which eventually carves ionized channels that might favor the escape of Lyman continuum radiation. The survival of some of the clusters would make them the progenitors of massive and relatively metal-poor globular clusters in the local universe.
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