Docetaxel given orally as monotherapy results in low bioavailability of <10%. Previous studies have indicated that the intestinal efflux pump P-glycoprotein (P-gp) prevents uptake from the gut ...resulting in low systemic exposure to docetaxel. The purpose of this study was to determine the degree of enhancement of the oral uptake of docetaxel on combination with orally administered OC144-093, a potent P-gp inhibitor. Furthermore, the safety of combined treatment was determined and whether known functional genetic polymorphisms of the MDR1 gene could be associated with variability in docetaxel pharmacokinetics was also investigated.
A proof of concept study was carried out in 12 patients with advanced solid tumors. Patients were randomized to receive one course of 100 mg oral docetaxel combined with 500 mg OC144-093 followed 2 weeks later by a second i.v. course of docetaxel at a flat dose of 100 mg, without OC144-093, or vice versa. This was followed by standard i.v. docetaxel treatment if indicated.
The apparent relative oral bioavailability of docetaxel was 26+/-8%. Orally administered docetaxel combined with oral OC144-093 resulted in a Cmax of 415+/-255 ng ml(-1), an AUC0-infinity of 844+/-753 ng h ml(-1) and kel of 0.810+/-0.296 h(-1). These values differed significantly from those following i.v. administration of docetaxel, with a Cmax of 2124+/-1054 ng ml(-1), an AUC0-infinity of 2571+/-1598 ng h ml(-1) and a kel of 1.318+/-0.785 h(-1) (P=0.003, P=0.006, P=0.016). The study medication was well tolerated and most of the adverse events possibly or probably related to OC144-093 and docetaxel were of CTC grade 1 and 2. One patient had a homozygous 3435T/T mutation, which is associated with low intestinal P-gp expression, and two other patients had a homozygous mutation on exon 21.
The relative apparent bioavailability of 26% was most likely caused by a significant effect of OC144-093 on the oral uptake of docetaxel. Large intrapatient and interpatient (pharmacokinetic) variation was found after oral as well as after i.v. administration of docetaxel. Higher plasma levels were observed after 100 mg i.v. docetaxel than after 100 mg oral docetaxel plus 500 mg oral OC144-093. The safety of the oral combination was good. More patients should be evaluated to determine the effect of P-gp single nucleotide polymorphisms on oral pharmacokinetic values of docetaxel.
Spatial resolution of laser micromachining of polymers can be improved with the use of femtosecond laser pulses. Due to the short interaction time, thermal effects are significantly reduced. ...Additionally, the non-linear character of the interaction of ultrashort laser pulses with transparent materials allows the modification inside their bulk also. However, this creates the challenge to accurately focus the laser beam in the surface when only surface ablation is required. Thus, this work presents a study of the laser ablation of a transparent polymer at different pulse energies and focusing positions controlled through z-scan transmittance measurements. Experiments were performed using an Yb:KYW laser with 450 fs pulses and 1027 nm wavelength. Morphological analysis of the polymer surface after irradiation was performed using scanning electron microscopy. Similar ablation craters were found for a range of sample positions around the beam waist. However, focused ion beam cross-sections of the craters unveil significant inner modifications under most of the focusing conditions leading to surface ablation. Hence, surface ablation without damaging the bulk material only occurs at critical positions where the beam waist is located slightly outside the sample. In situ monitoring of the sample position can be made through transmittance measurements.
SETTING: Tuberculosis (TB) control requires accurate knowledge of TB incidence, but few studies have been published on TB incidence using individual data from drug prescriptions.OBJECTIVE: To measure ...the estimated completeness of regional surveillance system data before and after
adding data from anti-tuberculosis drug prescriptions.DESIGN: We compiled data on all individuals who received specific anti-tuberculosis drugs from three sources-the passive surveillance system, the active surveillance system and the anti-tuberculosis drug prescription database-in
the Balearic Islands, Spain, between 2010 and 2012. We applied the capture-recapture method to measure completeness of data reporting. Statistical significance was set at P < 0.05, and 95% confidence intervals (CIs) were calculated.RESULTS: We detected 605 incident cases,
compared with an estimated incidence of 719 cases (95%CI 646-793), representing 84.1% data completeness. We detected 480 of an estimated 559 pulmonary TB cases (95%CI 501-617; 85.9% data completeness) and 125 of an estimated 161 extra-pulmonary TB cases (95%CI 113-211; 77.6%
data completeness).CONCLUSIONS: By adding a new source, we increased detection with respect to a previous study by 10.4% for all forms of TB, 9.7% for pulmonary TB and 13% for extra-pulmonary TB.
Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that presents as either an isolated diaphragm defect or as part of a complex disorder with a wide array of anomalies (complex ...CDH). Some patients with complex CDH display distinct craniofacial anomalies such as craniofrontonasal dysplasia or craniosynostosis, defined by the premature closure of cranial sutures. Using clinical whole exome sequencing (WES), we found a
missense variant in a patient with a left-sided congenital diaphragmatic hernia as well as sagittal suture craniosynostosis. We applied targeted sequencing of
in patients with craniosynostosis or with a combination of craniosynostosis and CDH. This resulted in three additional
missense mutations in patients with craniosynostosis. The phenotype of the patient with both CDH as well as craniosynostosis was similar to the phenotype of previously reported patients with
missense mutations. Although these findings imply that both craniosynostosis as well as CDH may be associated with
mutations, further studies are required to establish whether
variants are causative mutations for both conditions or if our finding was coincidental.
Context.
Thanks to the
Gaia
mission, it will be possible to determine the masses of approximately hundreds of large main belt asteroids with very good precision. We currently have diameter estimates ...for all of them that can be used to compute their volume and hence their density. However, some of those diameters are still based on simple thermal models, which can occasionally lead to volume uncertainties as high as 20–30%.
Aims.
The aim of this paper is to determine the 3D shape models and compute the volumes for 13 main belt asteroids that were selected from those targets for which
Gaia
will provide the mass with an accuracy of better than 10%.
Methods.
We used the genetic Shaping Asteroids with Genetic Evolution (SAGE) algorithm to fit disk-integrated, dense photometric lightcurves and obtain detailed asteroid shape models. These models were scaled by fitting them to available stellar occultation and/or thermal infrared observations.
Results.
We determine the spin and shape models for 13 main belt asteroids using the SAGE algorithm. Occultation fitting enables us to confirm main shape features and the spin state, while thermophysical modeling leads to more precise diameters as well as estimates of thermal inertia values.
Conclusions.
We calculated the volume of our sample of main-belt asteroids for which the
Gaia
satellite will provide precise mass determinations. From our volumes, it will then be possible to more accurately compute the bulk density, which is a fundamental physical property needed to understand the formation and evolution processes of small Solar System bodies.
Livestock-associated MRSA (MC398) has emerged and is related to an extensive reservoir in pigs and veal calves. Individuals with direct contact with these animals and their family members are known ...to have high MC398 carriage rates. Until now it was assumed that MC398 does not spread to individuals in the community without pig or veal calf exposure. To test this, we identified the proportion of MC398 in MRSA positive individuals without contact with pigs/veal calves or other known risk factors (MRSA of unknown origin; MUO).
In 17 participating hospitals, we determined during two years the occurrence of MC398 in individuals without direct contact with livestock and no other known risk factor (n = 271) and tested in a post analysis the hypothesis whether hospitals in pig-dense areas have higher proportions of MC398 of all MUO.
Fifty-six individuals (20.7%) without animal contact carried MC398. In hospitals with high pig-densities in the adherence area, the proportion of MC398 of all MUO was higher than this proportion in hospitals without pigs in the surroundings.
One fifth of the individuals carrying MUO carried MC398. So, MC398 is found in individuals without contact to pigs or veal calves. The way of transmission from the animal reservoir to these individuals is unclear, probably by human-to-human transmission or by exposure to the surroundings of the stables. Further research is needed to investigate the way of transmission.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The objective of our study was to validate free-breathing 2D inversion recovery delayed-enhancement MRI for the assessment of myocardial infarction compared with a breath-hold 3D technique.
...Institutional review board approval and written informed consent were obtained. Thirty-two patients (25 men, seven women; mean age, 68 years; age range, 39-84 years) underwent breath-hold gradient-echo 3D inversion-recovery delayed-enhancement MRI and free-breathing respiratory-triggered 2D inversion-recovery delayed-enhancement MRI of the heart (scanning time, 50-80 seconds). Infarct size was quantitatively analyzed as a percentage of the left ventricle. The location and transmural extent of myocardial infarction were assessed by visual scoring. Intraclass correlation and Bland-Altman analysis were used to evaluate the agreement between the techniques for infarct quantification. Kappa statistics were used to analyze the visual score.
Excellent agreement between the two techniques was observed for infarct quantification (intraclass correlation = 0.99 p < 0.01; mean difference +/- SD = 0.32% +/- 2.4%). The agreement in assessing transmural extent of infarction was good to excellent between the free-breathing technique and the 3D breath-hold technique (kappa varied between 0.70 and 0.96 for all segments). No regions of infarction were missed using the free-breathing approach.
The free-breathing 2D delayed-enhancement MRI sequence is a fast and reliable tool for detecting myocardial infarction.
Objective
To study the prevalence of attention‐deficit and hyperactivity disorder (ADHD) in adult patients with bipolar disorder (BD) and identify differential clinical features for a better ...diagnosis.
Method
A total of 163 euthymic bipolar out‐patients were screened for ADHD with the ASRS.V1 and the WURS at a BD Unit. Patients with a positive screening were assessed with the CAADID, at an ADHD unit. Sociodemographic and clinical features of the groups with and without ADHD were compared.
Results
Lifetime prevalence of comorbid ADHD was 17.9% (10.5% for adult ADHD and 7.4% for childhood ADHD). The BD + ADHD group showed more suicidal behaviour although less severe. Comorbidity was also more common, especially regarding substance use disorders. Nevertheless, these patients did not show more affective episodes or hospitalizations and suffered more atypical but less melancholic depression. However, they required more treatment with psychotherapy and valproate. One‐third of positive screenings at the ASRS were false; a severe course of BD was the hallmark of this subgroup.
Conclusion
Adult patients with BD and ADHD show differential clinical features, but not a more severe course of BD. Comorbidity with substance abuse is a big issue, deserving special clinical attention. Better screening tools are necessary to avoid overdiagnosis of comorbid ADHD in BD.
The emergence of SARS-CoV-2 antibody escape mutations highlights the urgent need for broadly neutralizing therapeutics. We previously identified a human monoclonal antibody, 47D11, capable of ...cross-neutralizing SARS-CoV-2 and SARS-CoV and protecting against the associated respiratory disease in an animal model. Here, we report cryo-EM structures of both trimeric spike ectodomains in complex with the 47D11 Fab. 47D11 binds to the closed receptor-binding domain, distal to the ACE2 binding site. The CDRL3 stabilizes the N343 glycan in an upright conformation, exposing a mutationally constrained hydrophobic pocket, into which the CDRH3 loop inserts two aromatic residues. 47D11 stabilizes a partially open conformation of the SARS-CoV-2 spike, suggesting that it could be used effectively in combination with other antibodies targeting the exposed receptor-binding motif. Together, these results reveal a cross-protective epitope on the SARS-CoV-2 spike and provide a structural roadmap for the development of 47D11 as a prophylactic or postexposure therapy for COVID-19.
PDF
