Miracle-dz/UniFAR-FTUs huggingface dataset:
European Paediatric Formulation Initiative (EuPFI)—Formulating Ideas for Better Medicines for Children

The European Paediatric Formulation Initiative (EuPFI), founded in 2007, aims to promote and facilitate the preparation of better and safe medicines for children through linking research and information dissemination. It brings together the capabilities of the industry, academics, hospitals, and regulators within a common platform in order to scope the solid understanding of the major issues, which will underpin the progress towards the future of paediatric medicines we want.The EuPFI was formed in parallel to the adoption of regulations within the EU and USA and has served as a community that drives research and dissemination through publications and the organisation of annual conferences. The membership and reach of this group have grown since its inception in 2007 and continue to develop and evolve to meet the continuing needs and ambitions of research into and development of age appropriate medicines. Five diverse workstreams (age-appropriate medicines, Biopharmaceutics, Administration Devices, Excipients and Taste Assessment & Taste Masking (TATM)) direct specific workpackages on behalf of the EuPFI. Furthermore, EuPFI interacts with multiple diverse professional groups across the globe to ensure efficient working in the area of paediatric medicines. Strong commitment and active involvement of all EuPFI stakeholders have proved to be vital to effectively address knowledge gaps related to paediatric medicines, discuss potential areas for further research and identify issues that need more attention and analysis in the future.
Quantitative measurement of microvascular permeability in human brain tumors achieved using dynamic contrast-enhanced MR imaging: correlation with histologic grade.

BACKGROUND AND PURPOSE Dynamic contrast-enhanced MR imaging may be used to quantify tissue fractional blood volume (fBV) and microvascular permeability. We tested this technique in patients with brain tumors to assess whether these measurements correlate with tumor histologic grade. METHODS Twenty-two patients with newly diagnosed gliomas underwent MR imaging followed by surgery. Imaging consisted of one pre- and six dynamic postcontrast 3D spoiled gradient-recalled acquisition in the steady state data sets after administration of a single dose (0.1 mmol/kg) of contrast material. Signal intensity changes in blood and tissue were kinetically analyzed using a bidirectional two-compartment model, yielding estimates of fBV (mL/cm3) and microvascular permeability (mL/100 cm3 per minute). Stained tumor specimens were scored on a four-point scale (1 = low grade, 4 = high grade). RESULTS Histologic examination revealed one grade 1, eight grade 2, seven grade 3, and six grade 4 tumors. fBV values ranged from 0.5% to 13.7%. Permeability values ranged from -0.4 to 18.8, with a strong correlation (r = 0.83) to tumor grade. Despite some overlap between the permeability values of specific tumors from different grades, differences in the mean were statistically significant. There was a weak correlation (r = 0.39) between estimated fBV and tumor grade, and no statistically significant difference among fBV values in any of the groups. CONCLUSION This relatively simple method of analysis provides quantitative estimates of fBV and microvascular permeability in human brain tumors, with the permeability being predictive of pathologic grade. The technique can be easily implemented on clinical scanners and may prove useful in the assessment of tumor biology and in therapeutic trials.
Paramagnetically induced residual dipolar couplings for solution structure determination of lanthanide binding proteins.

Lanthanides may substitute calcium in calcium-binding proteins, such as, for instance, EF-hand proteins. Paramagnetic lanthanides are capable of orienting the protein in high magnetic fields to an extent similar to that obtained by using orienting devices, and each lanthanide orients according to its magnetic susceptibility tensor. Here, Ce(3+), Tb(3+), Dy(3+), Ho(3+), Er(3+), Tm(3+), Yb(3+) in the C-terminal site of calbindin D(9k) have been investigated. Such systems provide (1)H-(15)N residual dipolar couplings (rdc) which can be used for solution structure determinations. Within the frame of optimizing the use of residual dipolar couplings for efficient solution structure determination, it is proposed here to use a number of lanthanides (e.g., >2) to obtain the orientations of the internuclear vectors with respect to an arbitrary reference system. This is facilitated by the independent knowledge of the magnetic susceptibility anisotropy tensor of each metal, obtained from the analysis of the pseudocontact shifts. A further module of the program PARAMAGNETIC-DYANA, called RDCDYANA-ANGLES, is developed to efficiently incorporate such rdc-derived orientations, instead of the rdc themselves, as constraints in the solution structure calculation. This strategy is absolutely general and can be extended to any other pair of dipole-dipole coupled nuclei. The effect of mobility is also assessed. In principle, information on the mobility can be obtained with a number of lanthanide ions >5, or by combining a smaller number of lanthanide ions with a few orienting devices.
The Utilization of Qualitative and Quantitative Data for Health Education Program Planning, Implementation, and Evaluation: A Spiral Approach

The process of development of a Dutch smoking prevention project is described. An essential feature of the project is the combination and interaction of qualitative and quantitative research methods. It is advocated that each method has its own contribution and can be considered as a separate methodology contributing to social science in general and health education research in particular. Combining the two approaches in a spiral approach will result in a synergistic effect, because of the interaction of both approaches. The results of both methods suggest that qualitative methods enhanced the generation of ideas and theories. Qualitative methods were used to formulate ideas for improving quantitative data gathering, analyzing and comparing ideas with respect to program development, and for testing the internal validity of a quantitative design. The quantitative method enabled testing of results in different groups and detecting detailed differences. It also provided information that one of the assumptions of the program, the development of a teacher independent program, was not completely realized. The major advantage of using both methods is that this provides feedback between assumptions and data, thus enhancing comparison of results and critical reflection during the whole project.
Laser, radiofrequency, and ethanol ablation for the management of thyroid nodules

Purpose of reviewThe majority of benign thyroid nodules are nearly asymptomatic, remain stable in size, and do not require treatment. However, a minority of patients with growing nodules may complain of local symptoms or have cosmetic concerns, and thus seek surgical consultation. Recent findingsThe timely use of ultrasound-guided minimally invasive procedures can change the natural history of benign enlarging thyroid nodules. The procedures produce persistent shrinkage of thyroid nodules and are associated with improvement of local symptoms. Among the various procedures, percutaneous ethanol injection represents the first-line treatment for relapsing thyroid cysts. In solid nonfunctioning nodules, laser and radiofrequency ablation produces a more than 50% reduction in nodular volume that remains persistent over several years. For hyperfunctioning nodules, thermal ablation techniques are not appropriate unless radioactive iodine is contraindicated or not accessible. SummaryMITs are best suited for the management of medium or large-sized nodules that are sonographically well visualized. Conversely, large nodules or nodular goiters that extend into the chest are difficult to treat. MITs are performed in outpatient clinics, are less expensive, and have a lower risk of complications, compared to surgery, and usually do not induce thyroid dysfunction. However, malignancy should be ruled out with a dedicated ultrasound neck assessment and repeat fine needle aspiration of the lesion before treatment.
Field Experiments in Corporate Sustainability Research

Experimental studies are a valuable tool to test effective strategies for encouraging sustainable behavior but have not been used much in corporate sustainability research. In this article, we describe the benefits and challenges of the randomized field experimental method for research in corporate sustainability. We draw on the examples of our own research in energy conservation behavior to illustrate some of the hurdles that need to be overcome for the successful implementation of field experiments.
Macroprudential tools, their limits and their connection with monetary policy

The first difference is that macroprudential policy is aimed at specific sectors or practices. In some respects, macroprudential policy harks back to the directed credit policies used by many advanced economies up to the 1970s, although these were used to channel credit to favoured sectors, as well as to constrain credit. The name is different, but the policies are similar. In many cases, it is old wine in new bottles. In contrast, monetary policy influences risk-taking more broadly, both within the domestic financial system but also across borders, and is harder to circumvent. New borrowers
A Neural Network-Based Multiplicative Actuator Fault Detection and Isolation of Nonlinear Systems

The problem of fault detection and isolation/identification (FDI) of nonlinear systems using neural networks is considered in this paper. The proposed FDI approach employs recurrent neural network-based observers for simultaneously detecting, isolating and identifying the severity of actuator faults in presence of disturbances and uncertainties in the model and sensory measurements. The neural network weights are updated based on a modified dynamic backpropagation scheme. The proposed FDI scheme does not rely on the availability of full state measurements. In most works in the literature the fault function acts as an additive term on the actuator, whereas in this work the fault acts as a multiplicative term. This will make the formal stability and convergence analysis of the overall FDI scheme nontrivial and challenging. Our stability analysis considers the presence of plant and sensor uncertainties through the use of Lyapunov's direct method with no restrictive assumptions on the system and/or the FDI algorithm. The performance of our proposed FDI approach is evaluated through simulations that are performed for two case studies, namely FDI of 1) reaction wheel type actuators that are commonly utilized in the attitude control subsystem (ACS) of a satellite and 2) actuators in a two-link flexible joint manipulator.
In Vitro Activity of Delafloxacin against Clinical Neisseria gonorrhoeae Isolates and Selection of Gonococcal Delafloxacin Resistance

ABSTRACT We evaluated the in vitro activity of delafloxacin against a panel of 117 Neisseria gonorrhoeae strains, including 110 clinical isolates collected from 2012 to 2015 and seven reference strains, compared with the activities of seven antimicrobials currently or previously recommended for treatment of gonorrhea. We examined the potential for delafloxacin to select for resistant mutants in ciprofloxacin-susceptible and ciprofloxacin-resistant N. gonorrhoeae. We characterized mutations in the gyrA, gyrB, parC, and parE genes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) by PCR and sequencing and by whole-genome sequencing. The MIC50, MIC90, and MIC ranges of delafloxacin were 0.06 μg/ml, 0.125 μg/ml, and ≤0.001 to 0.25 μg/ml, respectively. The frequency of spontaneous mutation ranged from 10−7 to <10−9. The multistep delafloxacin resistance selection of 30 daily passages resulted in stable resistant mutants. There was no obvious cross-resistance to nonfluoroquinolone comparator antimicrobials. A mutant with reduced susceptibility to ciprofloxacin (MIC, 0.25 μg/ml) obtained from the ciprofloxacin-susceptible parental strain had a novel Ser91Tyr alteration in the gyrA gene. We also identified new mutations in the gyrA and/or parC and parE genes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) of two mutant strains with elevated delafloxacin MICs of 1 μg/ml. Although delafloxacin exhibited potent in vitro activity against N. gonorrhoeae isolates and reference strains with diverse antimicrobial resistance profiles and demonstrated a low tendency to select for spontaneous mutants, it is important to establish the correlation between these excellent in vitro data and treatment outcomes through appropriate randomized controlled clinical trials.
Thiolated eudragit-based nanoparticles for oral insulin delivery: preparation, characterization, and evaluation using intestinal epithelial cells in vitro.

This work deals with the synthesis of insulin loaded nanoparticles (NPs) composed of thiolated Eudragit L100 (Eul-cys) and reduced glutathione (GSH) as potential nanocarriers for oral delivery of insulin. Perfectly spherical NPs with an average particle size of nearly 200-300 nm are prepared. The insulin release from Eul-cys/GSH and Eul-cys NPs in PBS (pH 7.4) shows that GSH can slightly decrease the release rate of insulin. Eul-cys in combination with GSH or sodium caprate (SC) is evaluated for its permeation enhancing effect of FITC-insulin using the Caco-2 monolayer and Caco-2/HT29-MTX co-cultured cells models. SC results in greater permeation enhancement compared to GSH. However, GSH proves to be less toxic. Paracellular transport of insulin represents the main mechanism by which the NPs facilitate insulin permeation through the intestinal epithelium, whereas a number of NPs are also taken up by the cells and release insulin within the cells.
Match Analysis of Elite Adolescent Team Handball Players

Chelly, MS, Hermassi, S, Aouadi, R, Khalifa, R, Van den Tillaar, R, Chamari, K, and Shephard, RJ. Match analysis of elite adolescent team handball players. J Strength Cond Res 25(9): 2410-2417, 2011—The purposes of this study were to examine the activity profile of elite adolescent players during regular team handball games and to compare the physical and motor performance of players between the first and second halves of a match. Activity patterns (video analysis) and heart-rate (HR) responses (telemetry) were monitored in top national-division adolescent players (18 men, aged 15.1 ± 0.6 years) throughout 6 regulation games (25-minute halves with a 10-minute interval). The total distance covered averaged 1,777 ± 264 m per game (7.4% less in the second than in the first half, p > 0.05). Players ran 170 ± 24 m at high intensity and 86 ± 12 m at maximal speed, with 32 ± 6 bouts of running (duration 2.3 ± 0.3 seconds) at speeds > 18 km·h−1; they stood still for 16% of the playing time. The mean HR during play was 172 ± 2 b·min−1 (82 ± 3% of maximal HR). Blood lactate concentrations at the end of the first and second halves were 9.7 ± 1.1 and 8.3 ± 0.9 mmol·L−1, respectively (difference p < 0.05). We conclude that adolescent handball players cover less distance and engage in fewer technical actions in the second half of a match. This indicates that team handball is physiologically very demanding. The practical implication is that coaches should seek to sustain performance in the second period of a game by modifying playing tactics and maximizing both aerobic and anaerobic fitness during training sessions.
Multiple pathogens in adult patients admitted with community-acquired pneumonia: a one year prospective study of 346 consecutive patients.

BACKGROUND: The purpose of this study was to assess the causes of community-acquired pneumonia in adult patients admitted to hospital. METHODS: A prospective study was performed on 346 consecutive adult patients (54% men) of mean (SD) 49.3 (19.5) years (range 17-94) admitted to a university affiliated regional hospital in southern Israel with community-acquired pneumonia over a period of one year. Convalescent serum samples were obtained from 308 patients (89%). The aetiological diagnosis for community-acquired pneumonia was based on positive blood cultures and/or significant changes in antibody titres to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, respiratory viruses, Coxiella burnetii, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella sp. RESULTS: The aetiology of community-acquired pneumonia was identified in 279 patients (80.6%). The distribution of causal agents was as follows: S pneumoniae, 148 patients (42.8%); M pneumoniae, 101 (29.2%); C pneumoniae, 62 (17.9%); Legionella sp, 56 (16.2%); respiratory viruses, 35 (10.1%); C burnetii, 20 (5.8%); H influenzae 19 (5.5%); and other causes, 21 patients (6.0%). In patients above the age of 55 years C pneumoniae was the second most frequent aetiological agent (25.5%). In 133 patients (38.4%) more than one causal agent was found. CONCLUSIONS: The causal agents for community-acquired pneumonia in Israel are different from those described in other parts of the world. In many of the patients more than one causal agent was found. In all these patients treatment should include a macrolide antibiotic, at least in the first stage of their illness.
Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial.

OBJECTIVE To determine the effects of low-dose prolonged methylprednisolone infusion on lung function in patients with early severe ARDS. DESIGN Randomized, double-blind, placebo-controlled trial. SETTING ICUs of five hospitals in Memphis. PARTICIPANTS Ninety-one patients with severe early ARDS (</= 72 h), 66% with sepsis. INTERVENTIONS Patients were randomized (2:1 fashion) to methylprednisolone infusion (1 mg/kg/d) vs placebo. The duration of treatment was up to 28 days. Infection surveillance and avoidance of paralysis were integral components of the protocol. MAIN OUTCOME MEASURE The predefined primary end point was a 1-point reduction in lung injury score (LIS) or successful extubation by day 7. RESULTS In intention-to-treat analysis, the response of the two groups (63 treated and 28 control) clearly diverged by day 7, with twice the proportion of treated patients achieving a 1-point reduction in LIS (69.8% vs 35.7%; p = 0.002) and breathing without assistance (53.9% vs 25.0%; p = 0.01). Treated patients had significant reduction in C-reactive protein levels, and by day 7 had lower LIS and multiple organ dysfunction syndrome scores. Treatment was associated with a reduction in the duration of mechanical ventilation (p = 0.002), ICU stay (p = 0.007), and ICU mortality (20.6% vs 42.9%; p = 0.03). Treated patients had a lower rate of infections (p = 0.0002), and infection surveillance identified 56% of nosocomial infections in patients without fever. CONCLUSIONS Methylprednisolone-induced down-regulation of systemic inflammation was associated with significant improvement in pulmonary and extrapulmonary organ dysfunction and reduction in duration of mechanical ventilation and ICU length of stay.
Drug chirality: a consideration of the significance of the stereochemistry of antimicrobial agents.

Approximately 25% of drugs are marketed as either racemates or mixtures of diastereoisomers. Such stereoisomers frequently differ in terms of their biological activity and pharmacokinetic profiles and the use of such mixtures may contribute to the adverse effects of the drug particularly if they are associated with the inactive or less active isomer. In recent years drug stereochemistry has become a significant issue for both the pharmaceutical industry and the regulatory authorities. The significance of stereoisomerism in antimicrobial agents is addressed in this review using examples drawn from the beta-lactams, as being representative of semisynthetic agents, and the quinolones, as examples of synthetic agents. Within these two groups of compounds it is clear that stereochemical considerations are of significance for an understanding of concentration effect relationships, selectivity in both action and inactivation and for an appreciation of the mode of action at a molecular level. In the case of some agents the use of a single isomer is precluded due to their facile epimerization, e.g. carbenicillin, in the case of others there are potential advantages with the use of single isomers, e.g. ofloxacin. However, in the case of latamoxef, a compound which undergoes in-vivo epimerization with a half-life similar to its apparent serum elimination half-life the situation is by-no-means clear cut. These agents emphasise the importance of considering each compound individually, i.e. on a case-by-case basis, before deciding to use a single isomer or stereoisomeric mixture.
Testing control of saltcedar seedlings using fall flooding

Because germination requirements of the exotic saltcedar (Tamarix ramosissima) and native cottonwood (Populus deltoides subsp. wislizenii) are similar, efforts to establish cottonwoods often result in concurrent establishment of saltcedars. We evaluated the success of fall flooding to reduce saltcedar seedling density in the Rio Grande floodplain of central New Mexico, USA. We also evaluated the effects of flooding on cottonwood seedlings. Six- to 8-week-old saltcedars and cottonwoods and 4-week-old saltcedars were completely submerged for a 30 day period from late August to late September. Effects of submergence were compared to a no submergence (control) treatment. Survival of 6- to 8-week-old saltcedar was 43.5±5.61% in the submerged treatment and 66.25±4.85% in the control. Survival of 4-week-old saltcedar was 2.0±2.0% and 65.75±8.74%, respectively, in submerged and control treatments. Cottonwood did not survive in the submergence treatment and 78.5±10.4% in the control. Because of the high mortality of cottonwood in response to complete submergence, flooding saltcedar seedlings may not be desirable when submergence of cottonwood seedlings will also occur.
Wild-type and Mutant Vacuolar Membranes Support pH-dependent Reassembly of the Yeast Vacuolar H+-ATPase in Vitro*

Treatment of the yeast vacuolar proton-translocating ATPase (H+-ATPase) with 300 mM KI in the presence of 5 mM MgATP results in a 90% inhibition of ATPase activity accompanied by removal of at least five of the peripheral subunits of the enzyme from the membrane. Functional reassembly of the enzyme, as indicated by reattachment of the peripheral subunits and a partial (30-70%) recovery of ATPase activity, could be achieved by dialysis of the stripped wild-type membranes to remove the KI and MgATP, but proved to be strongly pH-dependent, with optimal reassembly and recovery of activity occurring after dialysis at pH 5.5. Vacuolar membranes isolated from vma2Δ mutants, which lack one of the peripheral subunits of the enzyme, do not contain any of the peripheral subunits but are shown to contain assembled membrane (Vo) complexes. The vma2Δ mutant vacuoles are demonstrated to be competent for attachment of KI-stripped peripheral subunits and reactivation of ATPase activity. The results indicate that previously assembled Vo complexes are capable of inducing assembly of the peripheral subunits, both with each other and with the membrane subunits, and of activating the ATPase activity that resides in the peripheral subunits in a pH-dependent manner.