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PEG-Like Nanoprobes: Multimodal, Pharmacokinetically and Optically Tunable Nanomaterials
“PEG-like Nanoprobes” (PN’s) are pharmacokinetically and optically tunable nanomaterials whose disposition in biological systems can be determined by fluorescence or radioactivity. PN’s feature a unique design where a single PEG polymer surrounds a short fluorochrome and radiometal bearing peptide, and endows the resulting nanoprobe with pharmacokinetic control (based on molecular weight of the PEG selected) and optical tunability (based on the fluorochrome selected), while the chelate provides a radiolabeling option. PN’s were used to image brain capillary angiography (intravital 2-photon microscopy), tumor capillary permeability (intravital fluorescent microscopy), and the tumor enhanced permeability and retention (EPR) effect (111In-PN and SPECT). Clinical applications of PN’s include use as long blood half-life fluorochromes for intraoperative angiography, for measurements of capillary permeability in breast cancer lesions, and to image EPR by SPECT, for stratifying patient candidates for long-circulating nanomedicines that may utilize the EPR mechanism
Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease.
Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10-22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10-13) and osteoarthritis (P = 1.6 × 10-7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease
Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis
BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London
TBVAC2020 : advancing tuberculosis vaccines from discovery to clinical development
TBVAC2020 is a research project supported by the Horizon 2020 program of the European Commission (EC). It aims at the discovery and development of novel tuberculosis (TB) vaccines from preclinical research projects to early clinical assessment. The project builds on previous collaborations from 1998 onwards funded through the EC framework programs FP5, FP6, and FP7. It has succeeded in attracting new partners from outstanding laboratories from all over the world, now totaling 40 institutions. Next to the development of novel vaccines, TB biomarker development is also considered an important asset to facilitate rational vaccine selection and development. In addition, TBVAC2020 offers portfolio management that provides selection criteria for entry, gating, and priority settings of novel vaccines at an early developmental stage. The TBVAC2020 consortium coordinated by TBVI facilitates collaboration and early data sharing between partners with the common aim of working toward the development of an effective TB vaccine. Close links with funders and other consortia with shared interests further contribute to this goal
Safety and Efficacy of Digital Single-Operator Pancreatoscopy for Obstructing Pancreatic Ductal Stones
Translating Marine Animal Tracking Data into Conservation Policy and Management
There have been efforts around the globe to track individuals of many marine species and assess their movements and distribution with the putative goal of supporting their conservation and management. Determining whether, and how, tracking data have been successfully applied to address real-world conservation issues is however difficult. Here, we compile a broad range of case studies from diverse marine taxa to show how tracking data have helped inform conservation policy and management, including reductions in fisheries bycatch and vessel strikes, and the design and administration of marine protected areas and important habitats. Using these examples, we highlight pathways through which the past and future investment in collecting animal tracking data might be better used to achieve tangible conservation benefits
Early Release Science of the exoplanet WASP-39b with JWST NIRISS
Transmission spectroscopy provides insight into the atmospheric properties
and consequently the formation history, physics, and chemistry of transiting
exoplanets. However, obtaining precise inferences of atmospheric properties
from transmission spectra requires simultaneously measuring the strength and
shape of multiple spectral absorption features from a wide range of chemical
species. This has been challenging given the precision and wavelength coverage
of previous observatories. Here, we present the transmission spectrum of the
Saturn-mass exoplanet WASP-39b obtained using the SOSS mode of the NIRISS
instrument on the JWST. This spectrum spans m in wavelength and
reveals multiple water absorption bands, the potassium resonance doublet, as
well as signatures of clouds. The precision and broad wavelength coverage of
NIRISS-SOSS allows us to break model degeneracies between cloud properties and
the atmospheric composition of WASP-39b, favoring a heavy element enhancement
("metallicity") of the solar value, a sub-solar
carbon-to-oxygen (C/O) ratio, and a solar-to-super-solar potassium-to-oxygen
(K/O) ratio. The observations are best explained by wavelength-dependent,
non-gray clouds with inhomogeneous coverage of the planet's terminator.Comment: 48 pages, 12 figures, 2 tables. Under review at Natur
Developing Clinical and Research Priorities for Pain and Psychological Features in People With Patellofemoral Pain:An International Consensus Process With Health Care Professionals
OBJECTIVE: To decide clinical and research priorities on pain features and psychological factors in persons with patellofemoral pain. DESIGN: Consensus development process. METHODS: We undertook a 3-stage process consisting of (1) updating 2 systematic reviews on quantitative sensory testing of pain features and psychological factors in patellofemoral pain, (2) an online survey of health care professionals and persons with patellofemoral pain, and (3) a consensus meeting with expert health care professionals. Participants responded that they agreed, disagreed, or were unsure that a pain feature or psychological factor was important in clinical practice or as a research priority. Greater than 70% participant agreement was required for an item to be considered important in clinical practice or a research priority. RESULTS: Thirty-five health care professionals completed the survey, 20 of whom attended the consensus meeting. Thirty persons with patellofemoral pain also completed the survey. The review identified 5 pain features and 9 psychological factors—none reached 70% agreement in the patient survey, so all were considered at the meeting. Afte the meeting, pain catastrophizing, fear-avoidance beliefs, and pain self-efficacy were the only factors considered clinically important. All but the therma pain tests and 3 psychological factors were consid ered research priorities. CONCLUSION: Pain catastrophizing, pain self-efficacy, and fear-avoidance beliefs were factors considered important in treatment planning, clinical examination, and prognostication. Quantitative sensory tests for pain were not regarded as clinically important but were deemed to be research priorities, as were most psychological factors.</p
Association of Upfront Peptide Receptor Radionuclide Therapy With Progression-Free Survival Among Patients With Enteropancreatic Neuroendocrine Tumors
open57noIMPORTANCE Data about the optimal timing for the initiation of peptide receptor radionuclide
therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors
are lacking.
OBJECTIVE To evaluate the association of upfront PRRT vs upfront chemotherapy or targeted
therapy with progression-free survival (PFS) among patients with advanced enteropancreatic
neuroendocrine tumors who experienced disease progression after treatment with somatostatin
analogues (SSAs).
DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study analyzed the
clinical records from 25 Italian oncology centers for patients aged 18 years or older who had
unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic
neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after
experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1,
2020. Propensity score matching was done to minimize the selection bias.
EXPOSURES Upfront PRRT or upfront chemotherapy or targeted therapy.
MAIN OUTCOMES AND MEASURES The main outcome was the difference in PFS among patients
who received upfront PRRT vs among those who received upfront chemotherapy or targeted
therapy. A secondary outcome was the difference in overall survival between these groups. Hazard
ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for
relevant factors associated with PFS and were corrected for interaction with these factors.
RESULTS Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329
(64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targeted
therapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8]
years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in the
chemotherapy or targeted therapy group in the unmatched (2.5 years [95%CI, 2.3-3.0 years] vs 0.7
years [95%CI, 0.5-1.0 years]; HR, 0.35 [95%CI, 0.28-0.44; P < .001]) and matched (2.2 years [95%
CI, 1.8-2.8 years] vs 0.6 years [95%CI, 0.4-1.0 years]; HR, 0.37 [95%CI, 0.27-0.51; P < .001])
populations. No significant differences were shown in median overall survival between the PRRT and chemotherapy or targeted therapy groups in the unmatched (12.0 years [95%CI, 10.7-14.1 years] vs
11.6 years [95%CI, 9.1-13.4 years]; HR, 0.81 [95%CI, 0.62-1.06; P = .11]) and matched (12.2 years [95%
CI, 9.1-14.2 years] vs 11.5 years [95%CI, 9.2-17.9 years]; HR, 0.83 [95%CI, 0.56-1.24; P = .36])
populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37;
95%CI, 0.26-0.51; P < .001) in multivariable analysis. After adjustment of values for interaction,
upfront PRRT was associated with longer PFS regardless of tumor functional status (functioning:
adjusted HR [aHR], 0.39 [95%CI, 0.27-0.57]; nonfunctioning: aHR, 0.29 [95%CI, 0.16-0.56]), grade
of 1 to 2 (grade 1: aHR, 0.21 [95%CI, 0.12-0.34]; grade 2: aHR, 0.52 [95%CI, 0.29-0.73]), and site of
tumor origin (pancreatic: aHR, 0.41 [95%CI, 0.24-0.61]; intestinal: aHR, 0.19 [95%CI, 0.11-0.43])
(P < .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95%CI,
0.12-1.37; P = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95%CI,
0.29-1.43; P = .31).
CONCLUSIONS AND RELEVANCE In this cohort study, treatment with upfront PRRT in patients
with enteropancreatic neuroendocrine tumors who had experienced disease progression with SSA
treatment was associated with significantly improved survival outcomes compared with upfront
chemotherapy or targeted therapy. Further research is needed to investigate the correct strategy,
timing, and optimal specific sequence of these therapeutic options.openPusceddu, Sara; Prinzi, Natalie; Tafuto, Salvatore; Ibrahim, Toni; Filice, Angelina; Brizzi, Maria Pia; Panzuto, Francesco; Baldari, Sergio; Grana, Chiara M.; Campana, Davide; Davì, Maria Vittoria; Giuffrida, Dario; Zatelli, Maria Chiara; Partelli, Stefano; Razzore, Paola; Marconcini, Riccardo; Massironi, Sara; Gelsomino, Fabio; Faggiano, Antongiulio; Giannetta, Elisa; Bajetta, Emilio; Grimaldi, Franco; Cives, Mauro; Cirillo, Fernando; Perfetti, Vittorio; Corti, Francesca; Ricci, Claudio; Giacomelli, Luca; Porcu, Luca; Di Maio, Massimo; Seregni, Ettore; Maccauro, Marco; Lastoria, Secondo; Bongiovanni, Alberto; Versari, Annibale; Persano, Irene; Rinzivillo, Maria; Pignata, Salvatore Antonio; Rocca, Paola Anna; Lamberti, Giuseppe; Cingarlini, Sara; Puliafito, Ivana; Ambrosio, Maria Rosaria; Zanata, Isabella; Bracigliano, Alessandra; Severi, Stefano; Spada, Francesca; Andreasi, Valentina; Modica, Roberta; Scalorbi, Federica; Milione, Massimo; Sabella, Giovanna; Coppa, Jorgelina; Casadei, Riccardo; Di Bartolomeo, Maria; Falconi, Massimo; de Braud, FilippoPusceddu, Sara; Prinzi, Natalie; Tafuto, Salvatore; Ibrahim, Toni; Filice, Angelina; Brizzi, Maria Pia; Panzuto, Francesco; Baldari, Sergio; Grana, Chiara M.; Campana, Davide; Davì, Maria Vittoria; Giuffrida, Dario; Zatelli, Maria Chiara; Partelli, Stefano; Razzore, Paola; Marconcini, Riccardo; Massironi, Sara; Gelsomino, Fabio; Faggiano, Antongiulio; Giannetta, Elisa; Bajetta, Emilio; Grimaldi, Franco; Cives, Mauro; Cirillo, Fernando; Perfetti, Vittorio; Corti, Francesca; Ricci, Claudio; Giacomelli, Luca; Porcu, Luca; Di Maio, Massimo; Seregni, Ettore; Maccauro, Marco; Lastoria, Secondo; Bongiovanni, Alberto; Versari, Annibale; Persano, Irene; Rinzivillo, Maria; Pignata, Salvatore Antonio; Rocca, Paola Anna; Lamberti, Giuseppe; Cingarlini, Sara; Puliafito, Ivana; Ambrosio, Maria Rosaria; Zanata, Isabella; Bracigliano, Alessandra; Severi, Stefano; Spada, Francesca; Andreasi, Valentina; Modica, Roberta; Scalorbi, Federica; Milione, Massimo; Sabella, Giovanna; Coppa, Jorgelina; Casadei, Riccardo; Di Bartolomeo, Maria; Falconi, Massimo; de Braud, Filipp
A broadband thermal emission spectrum of the ultra-hot Jupiter WASP-18b
Close-in giant exoplanets with temperatures greater than 2,000 K (''ultra-hot
Jupiters'') have been the subject of extensive efforts to determine their
atmospheric properties using thermal emission measurements from the Hubble and
Spitzer Space Telescopes. However, previous studies have yielded inconsistent
results because the small sizes of the spectral features and the limited
information content of the data resulted in high sensitivity to the varying
assumptions made in the treatment of instrument systematics and the atmospheric
retrieval analysis. Here we present a dayside thermal emission spectrum of the
ultra-hot Jupiter WASP-18b obtained with the NIRISS instrument on JWST. The
data span 0.85 to 2.85 m in wavelength at an average resolving power of
400 and exhibit minimal systematics. The spectrum shows three water emission
features (at 6 confidence) and evidence for optical opacity,
possibly due to H, TiO, and VO (combined significance of 3.8).
Models that fit the data require a thermal inversion, molecular dissociation as
predicted by chemical equilibrium, a solar heavy element abundance
(''metallicity'', M/H = 1.03 solar), and a
carbon-to-oxygen (C/O) ratio less than unity. The data also yield a dayside
brightness temperature map, which shows a peak in temperature near the
sub-stellar point that decreases steeply and symmetrically with longitude
toward the terminators.Comment: JWST ERS bright star observations. Uploaded to inform JWST Cycle 2
proposals. Manuscript under review. 50 pages, 14 figures, 2 table
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