Background. An important requirement for an effective antibiotic stewardship program is the ability to measure appropriateness of antibiotic use. The aim of this study was to develop quality ...indicators (QIs) that can be used to measure appropriateness of antibiotic use in the treatment of all bacterial infections in hospitalized adult patients. Methods. A RAND-modified Delphi procedure was used to develop a set of QIs. Potential QIs were retrieved from the literature. In 2 questionnaire mailings with an in-between face-to-face consensus meeting, an international multidisciplinary expert panel of 17 experts appraised and prioritized these potential QIs. Results. The literature search resulted in a list of 24 potential QIs. Nine QIs describing recommended care at patient level were selected: (1) take 2 blood cultures, (2) take cultures from suspected sites of infection, (3) prescribe empirical antibiotic therapy according to local guideline, (4) change empirical to pathogen-directed therapy, (5) adapt antibiotic dosage to renal function, (6) switch from intravenous to oral, (7) document antibiotic plan, (8) perform therapeutic drug monitoring, and (9) discontinue antibiotic therapy if infection is not confirmed. Two QIs describing recommended care at the hospital level were also selected: (1) a local antibiotic guideline should be present, and (2) these local guidelines should correspond to the national antibiotic guidelines. Conclusions. The selected QIs can be used in antibiotic stewardship programs to determine for which aspects of antibiotic use there is room for improvement. At this moment we are testing the clinimetric properties of these QIs in 1800 hospitalized patients, in 22 Dutch hospitals.
Alarmins S100A8/A9 regulate pathology in experimental osteoarthritis (OA). Paquinimod is an immunomodulatory compound preventing S100A9 binding to TLR-4. We investigated the effect of paquinimod on ...experimental OA and human OA synovium.
Two OA mouse models differing in level of synovial activation were treated prophylactic with paquinimod. Synovial thickening, osteophyte size and cartilage damage were measured histologically, using an arbitrary score, adapted Pritzker OARSI score or imaging software, respectively. Human OA synovia were stimulated with S100A9, with or without paquinimod.
Paquinimod treatment of collagenase-induced OA (CIOA) resulted in significantly reduced synovial thickening (57%), osteophyte size at the medial femur (66%) and cruciate ligaments (67%) and cartilage damage at the medial tibia (47%) and femur (75%; n=7, untreated n=6). In contrast, paquinimod did not reduce osteophyte size and reduced cartilage damage at one location only in destabilised medial meniscus, an OA model with considerably lower synovial activation compared with CIOA. In human OA synovium, paquinimod blocked proinflammatory (interleukin (IL)-6, IL-8, tumour necrosis factor-α) and catabolic (matrix metalloproteinases 1 and 3) factors induced by S100A9 (n=5).
Prophylactic treatment of paquinimod reduces synovial activation, osteophyte formation and cartilage damage in experimental OA with high synovial activation (CIOA) and ameliorates pathological effects of S100A9 in OA synovium ex vivo.
We developed European guidelines to optimise phenylketonuria (PKU) care. To develop the guidelines, we did a literature search, critical appraisal, and evidence grading according to the Scottish ...Intercollegiate Guidelines Network method. We used the Delphi method when little or no evidence was available. From the 70 recommendations formulated, in this Review we describe ten that we deem as having the highest priority. Diet is the cornerstone of treatment, although some patients can benefit from tetrahydrobiopterin (BH4). Untreated blood phenylalanine concentrations determine management of people with PKU. No intervention is required if the blood phenylalanine concentration is less than 360 μmol/L. Treatment is recommended up to the age of 12 years if the phenylalanine blood concentration is between 360 μmol/L and 600 μmol/L, and lifelong treatment is recommended if the concentration is more than 600 μmol/L. For women trying to conceive and during pregnancy (maternal PKU), untreated phenylalanine blood concentrations of more than 360 μmol/L need to be reduced. Treatment target concentrations are as follows: 120-360 μmol/L for individuals aged 0-12 years and for maternal PKU, and 120-600 μmol/L for non-pregnant individuals older than 12 years. Minimum requirements for the management and follow-up of patients with PKU are scheduled according to age, adherence to treatment, and clinical status. Nutritional, clinical, and biochemical follow-up is necessary for all patients, regardless of therapy.
Planet Hunters IX. KIC 8462852 – where's the flux? Boyajian, T. S; LaCourse, D. M; Rappaport, S. A ...
Monthly notices of the Royal Astronomical Society,
04/2016, Letnik:
457, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Over the duration of the Kepler mission, KIC 8462852 was observed to undergo irregularly shaped, aperiodic dips in flux of up to ∼20 per cent. The dipping activity can last for between 5 and 80 d. We ...characterize the object with high-resolution spectroscopy, spectral energy distribution fitting, radial velocity measurements, high-resolution imaging, and Fourier analyses of the Kepler light curve. We determine that KIC 8462852 is a typical main-sequence F3 V star that exhibits no significant IR excess, and has no very close interacting companions. In this paper, we describe various scenarios to explain the dipping events observed in the Kepler light curve. We confirm that the dipping signals in the data are not caused by any instrumental or data processing artefact, and thus are astrophysical in origin. We construct scenario-independent constraints on the size and location of a body in the system that are needed to reproduce the observations. We deliberate over several assorted stellar and circumstellar astrophysical scenarios, most of which have problems explaining the data in hand. By considering the observational constraints on dust clumps in orbit around a normal main-sequence star, we conclude that the scenario most consistent with the data in hand is the passage of a family of exocomet or planetesimal fragments, all of which are associated with a single previous break-up event, possibly caused by tidal disruption or thermal processing. The minimum total mass associated with these fragments likely exceeds 10−6 M⊕, corresponding to an original rocky body of >100 km in diameter. We discuss the necessity of future observations to help interpret the system.
MR-guided HIFU ablation is a promising technique for the non-invasive treatment of breast cancer. A phase I study was performed to assess the safety and treatment accuracy and precision of MR-HIFU ...ablation in breast cancer patients () using a newly developed MR-HIFU platform dedicated to applications in the breast. In this paper a technical analysis of the performance of the dedicated breast MR-HIFU system during breast tumors ablation is described. The main points of investigation were the spatial targeting accuracy and precision of the system and the performance of real-time respiration-corrected MR thermometry. The mean targeting accuracy was in the range of 2.4-2.6 mm, whereas the mean targeting precision was in the range of 1.5-1.8 mm. To correct for respiration-induced magnetic field fluctuations during MR temperature mapping a look-up-table (LUT)-based correction method was used. An optimized procedural sedation protocol in combination with the LUT-based correction method allowed for precise MR thermometry during the ablation procedure (temperature standard deviation <3 °C). No unwanted heating in the near field (i.e. skin) nor in the far field (pectoral muscle) was detected. The newly developed dedicated breast MR-HIFU system allows for safe, accurate and precise ablation of breast tumors.
Microglia nodules (HLA-DR
cell clusters) are associated with brain pathology. In this post-mortem study, we investigated whether they represent the first stage of multiple sclerosis (MS) lesion ...formation. We show that microglia nodules are associated with more severe MS pathology. Compared to microglia nodules in stroke, those in MS show enhanced expression of genes previously found upregulated in MS lesions. Furthermore, genes associated with lipid metabolism, presence of T and B cells, production of immunoglobulins and cytokines, activation of the complement cascade, and metabolic stress are upregulated in microglia nodules in MS. Compared to stroke, they more frequently phagocytose oxidized phospholipids and possess a more tubular mitochondrial network. Strikingly, in MS, some microglia nodules encapsulate partially demyelinated axons. Taken together, we propose that activation of microglia nodules in MS by cytokines and immunoglobulins, together with phagocytosis of oxidized phospholipids, may lead to a microglia phenotype prone to MS lesion formation.
Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has ...proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients.
Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018.
Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome.
This study describes the natural history of classic galactosemia based on the hitherto largest data set.
Alarmins S100A8 and S100A9 are major products of activated macrophages regulating cartilage damage and synovial activation during murine and human osteoarthritis (OA). In the current study, we ...investigated whether S100A8 and S100A9 are involved in osteophyte formation during experimental OA and whether S100A8/A9 predicts osteophyte progression in early human OA.
OA was elicited in S100A9-/- mice in two experimental models that differ in degree of synovial activation. Osteophyte size, S100A8, S100A9 and VDIPEN neoepitope was measured histologically. Chondrogenesis was induced in murine mesenchymal stem cells in the presence of S100A8. Levels of S100A8/A9 were determined in plasma of early symptomatic OA participants of the Cohort Hip and Cohort Knee (CHECK) cohort study and osteophytes measured after 2 and 5 years.
Osteophyte size was drastically reduced in S100A9-/- mice in ligaments and at medial femur and tibia on days 21 and 42 of collagenase-induced OA, in which synovial activation is high. In contrast, osteophyte size was not reduced in S100A9-/- mice during destabilised medial meniscus OA, in which synovial activation is scant. S100A8 increased expression and activation of matrix metalloproteinases during micromass chondrogenesis, thereby possibly increasing cartilage matrix remodelling allowing for larger osteophytes. Interestingly, early symptomatic OA participants of the CHECK study with osteophyte progression after 2 and 5 years had elevated S100A8/A9 plasma levels at baseline, while C-reactive protein, erythrocyte sedimentation rate and cartilage oligomeric matrix protein were not elevated at baseline.
S100A8/A9 aggravate osteophyte formation in experimental OA with high synovial activation and may be used to predict osteophyte progression in early symptomatic human OA.
Intraoperative ultrasound (IOUS) can be used in the operation theatre for localization of non-palpable breast cancers. In this prospective cohort study, we compared the yield of IOUS to guidewire ...localization (GWL). A total of 258 consecutive patients with non-palpable invasive breast cancer underwent breast conserving surgery between 1999 and 2010. GWL was performed in 138 (54 %) and IOUS in 120 (46 %) patients. Tumor dimensions, resection volume, margin status and re-excision rates were compared by means of multivariate regression analysis. The groups were similar in terms of age, histological subtype and presence of DCIS. Lesions in the IOUS group were larger (1.24 vs. 0.98 cm,
P
< 0.001), while microcalcifications were more common in the GWL group (19 vs. 3 %,
P
< 0.001). Even after stratification for tumor diameter, presence of DCIS and findings on mammography, resection volumes were similar in both groups. Tumor-free resection margins were obtained in >93 % of patients (93.5 % with GWL vs. 93.3 % with IOUS,
P
= 0.958) and re-excision was performed in 11 % of patients undergoing GWL and 12.5 % of patients undergoing IOUS (
P
= 0.684). For localization of non-palpable breast cancer, IOUS is a reliable alternative to GWL, as it achieves similar results in terms of complete tumor removal, re-excision rate and excised volume.
Delamination between a coating and a substrate is often an undesired phenomenon, for which predictive numerical schemes are required. The interface between the coating and the substrate is commonly ...described by cohesive zones, for which several different cohesive zone laws have been proposed in literature. Among the widening class of developed cohesive zone laws this paper focuses on the most frequently adopted law of Xu and Needleman. It is shown that this cohesive zone law needs improvement in order to describe a mixed-mode decohesion process. This conclusion is based on investigations of the influence of the coupling parameters and the assessment of the work-of-separation under mixed-mode conditions. Remedies for this problem with the Xu and Needleman law are not yet available in literature. An alternative exponential cohesive zone law, derived from the law of Xu and Needleman, is presented, which correctly describes mixed-mode decohesion. Attention is also given to the practical determination of all the parameters involved.
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