In one sense, the problem of finding the densest packing of congruent circles in a square is easy to understand. But on closer inspection, this problem reveals itself to be an interesting challenge ...of discrete and computational geometry with all its surprising structural forms and regularities. This book summarizes results achieved in solving the circle packing problem over the past few years, providing the reader with a comprehensive view of both theoretical and computational achievements. Typically illustrations of problem solutions are shown, elegantly displaying the results obtained.Beyond the theoretically challenging character of the problem, the solution methods developed in the book also have many practical applications.One especially important feature of the book is the inclusion on an enclosed CD of all the open source programming codes used. Since the codes can be worked with directly, they will enable the reader to improve on them and solve problem instances that still remain challenging, or to use them as a starting point for solving related application problems.
Background and purpose
In Parkinson's disease (PD), the course of the disorder is highly variable between patients. Well‐designed, prospective studies for identifying PD progression biomarkers are ...necessary. Our aim was to show the results of baseline evaluations of an ongoing global PD project, COPPADIS‐2015 (Cohort of Patients with PArkinson's DIsease in Spain, 2015).
Methods
This was an observational, descriptive, nationwide study (Spain). The recruitment period ended in October 2017. Baseline evaluation included more than 15 validated scales and complementary studies in a subgroup of participants.
Results
In total, 1174 subjects from 35 centres were considered valid for baseline analysis: 694 patients (62.6 ± 8.9 years old, 60.3% males), 273 caregivers (58.5 ± 11.9 years old, 31.8% males) and 207 controls (61 ± 8.3 years old, 49.5% males). The mean disease duration was 5.5 ± 4.4 years. Hoehn and Yahr stage was 1 or 2 in 90.7% of the patients whilst 33.9% and 18.1% of them presented motor fluctuations and dyskinesias, respectively. The mean Non‐Motor Symptoms Scale total score was 45.4 ± 38.1, and 30.4% of the patients presented cognitive impairment, 16.1% major depression, 12.7% impulse control disorder, 7.2% compulsive behaviour, 57.2% pain and 13.2% falls. Compared to the control group, PD patients presented a significantly higher burden of non‐motor symptoms and a worse quality of life. More than 300 subjects conducted complementary studies (serum biomarkers, genetic and neuroimaging).
Conclusions
Parkinson's disease is a complex disorder and different non‐motor symptoms are frequently present and are more prevalent than in controls. In real clinical practice it is important to ask for them.
Resumen La enfermedad de Crohn es una patología inflamatoria que afecta a cualquier parte del tracto gastrointestinal, aunque puede tener manifestaciones sistémicas y extraintestinales. Los fármacos ...biológicos se usan en pacientes con enfermedad de Crohn moderada-severa refractarios a terapias previas. Existen reacciones psoriasiformes paradójicas asociadas a tratamientos biológicos que actúan sobre el factor de necrosis tumoral (anti-TNF α), como adalimumab. Por otra parte, ustekinumab ha sido descrita como una alternativa terapéutica eficaz con un favorable perfil de seguridad en pacientes con co-morbilidades y/o reacciones de hipersensibilidad a otros fármacos. La colaboración multidisciplinar de diferentes profesionales sanitarios permite la identificación de eventos adversos poco frecuentes, como es la reacción psoriasiforme paradójica, y la optimización terapéutica de pacientes complejos. Este trabajo permite profundizar en la experiencia clínica y terapéutica de una colaboración multidisciplinar en una paciente complicada diagnosticada de enfermedad de Crohn, con reacción psoriasiforme paradójica secundaria a adalimumab.
A recent study shows that a multifaceted strategy using an individualised intra-abdominal pressure titration strategy during colorectal laparoscopic surgery results in an acceptable workspace at low ...intra-abdominal pressure in most patients. The multifaceted strategy, focused on lower to individualised intra-abdominal pressures, includes prestretching the abdominal wall during initial insufflation, deep neuromuscular blockade, low tidal volume ventilation settings and a modified lithotomy position. The study presented here tests the hypothesis that this strategy improves outcomes of patients scheduled for colorectal laparoscopic surgery.
The Individualized Pneumoperitoneum Pressure in Colorectal Laparoscopic Surgery versus Standard Therapy (IPPCollapse-II) study is a multicentre, two-arm, parallel-group, single-blinded randomised 1:1 clinical study that runs in four academic hospitals in Spain. Patients scheduled for colorectal laparoscopic surgery with American Society of Anesthesiologists classification I to III who are aged > 18 years and are without cognitive deficits are randomised to an individualised pneumoperitoneum pressure strategy (the intervention group) or to a conventional pneumoperitoneum pressure strategy (the control group). The primary outcome is recovery assessed with the Post-operative Quality of Recovery Scale (PQRS) at postoperative day 1. Secondary outcomes include PQRS score in the post anaesthesia care unit and at postoperative day 3, postoperative complications until postoperative day 28, hospital length of stay and process-related outcomes.
The IPPCollapse-II study will be the first randomised clinical study that assesses the impact of an individualised pneumoperitoneum pressure strategy focused on working with the lowest intra-abdominal pressure during colorectal laparoscopic surgery on relevant patient-centred outcomes. The results of this large study, to be disseminated through conference presentations and publications in international peer-reviewed journals, are of ultimate importance for optimising the care and safety of laparoscopic abdominal surgery. Selection of patient-reported outcomes as the primary outcome of this study facilitates the translation into clinical practice. Access to source data will be made available through anonymised datasets upon request and after agreement of the Steering Committee of the IPPCollapse-II study.
ClinicalTrials.gov, NCT02773173 . Registered on 16 May 2016. EudraCT, 2016-001693-15. Registered on 8 August 2016.
The production of a $W$ boson in association with a single charm quark is studied using 140 fb–1 of $\sqrt{s}$ = $13$ $\mathrm{TeV}$ proton-proton collision data collected with the ATLAS detector at ...the Large Hadron Collider. The charm quark is tagged by the presence of a charmed hadron reconstructed with a secondary-vertex fit. The $W$ boson is reconstructed from the decay to either an electron or a muon and the missing transverse momentum present in the event. The charmed mesons reconstructed are D+ → K– π+ π+ and D*+ → D0 π+ → (K– π+) π+ and the charge conjugate decays in the fiducial regions where $p$T($e,μ$) > 30 GeV, |$η(e,μ)$| < 2.5, $p$T (D(*)) > 8 GeV, and |$η$(D(*))| < 2.2. The integrated and normalized differential cross sections as a function of the pseudorapidity of the lepton from the $W$ boson decay, and of the transverse momentum of the charmed hadron, are extracted from the data using a profile likelihood fit. The measured total fiducial cross sections are ${σ}_{fid}^{OS – SS}$ (W– + D+) = 50.2 ± 0.2 ${(stat)}_{–2.3}^{+2.4}$(syst) pb, ${σ}_{fid}^{OS – SS}$ (W+ + D–) = 48.5 ± 0.2 ${(stat)}_{–2.2}^{+2.3}$(syst) pb, ${σ}_{fid}^{OS – SS}$ (W– + D*+) = 51.1 ± 0.4 ${(stat)}_{–1.8}^{+1.9}$(syst) pb, ${σ}_{fid}^{OS – SS}$ (W+ + D*–) = 50.0 ± 0.4 ${(stat)}_{–1.8}^{+1.9}$(syst) pb. Results are compared with the predictions of next-to-leading-order quantum chromodynamics calculations performed using state-of-the-art parton distribution functions. Additionally, the ratio of charm to anticharm production cross sections is studied to probe the $s$-$\bar{s}$ quark asymmetry. The ratio is found to be ${R}_{c}^{±}$= 0.971 ± 0.006 (stat) ± 0.011 (syst). The ratio and cross-section measurements are consistent with the predictions obtained with parton distribution function sets that have a symmetric $s$-$\bar{s}$ sea, indicating that any $s$-$\bar{s}$ asymmetry in the Bjorken-x region relevant for this measurement is small.
The Svalbard archipelago is particularly sensitive to climate change due to the relatively low altitude of its main ice fields and its geographical location in the higher North Atlantic, where the ...effect of Arctic amplification is more significant. The largest temperature increases have been observed during winter, but increasing summer temperatures, above the melting point, have led to increased glacier melt. Here, we evaluate the impact of this increased melt on the preservation of the oxygen isotope (δ18O) signal in firn records. δ18O is commonly used as a proxy for past atmospheric temperature reconstructions, and, when preserved, it is a crucial parameter to date and align ice cores. By comparing four different firn cores collected in 2012, 2015, 2017 and 2019 at the top of the Holtedahlfonna ice field (1100 m a.s.l.), we show a progressive deterioration of the isotope signal, and we link its degradation to the increased occurrence and intensity of melt events. Our findings indicate that, starting from 2015, there has been an escalation in melting and percolation resulting from changes in the overall atmospheric conditions. This has led to the deterioration of the climate signal preserved within the firn or ice. Our observations correspond with the model's calculations, demonstrating an increase in water percolation since 2014, potentially reaching deeper layers of the firn. Although the δ18O signal still reflects the interannual temperature trend, more frequent melting events may in the future affect the interpretation of the isotopic signal, compromising the use of Svalbard ice cores. Our findings highlight the impact and the speed at which Arctic amplification is affecting Svalbard's cryosphere.
Background and importanceOn the basis of resolution 189/2018 published by our city health council, the hospital pharmacy service was entrusted with the centralisation of the procedure for the ...acquisition, compounding, distribution and dispensing of methadone to drug addicts in integral attention centres. In order to improve and increase the beyond use date (BUD) of methadone oral solutions, we carried out a physicochemical stability study.Aim and objectivesTo develop an analytical method and validation to carry out a physicochemical stability study of two oral solutions of methadone to increase their BUD. Method development should be made in an effective and reproducible manner.Material and methodsThe study was carried out on two formulations of methadone 10 mg/mL, which were prepared with and without parabens as preservatives. A high performance liquid chromatography (HPLC) Agilent 1100 was used, provided with a quaternary pump and an ultraviolet diode array detector to determine methadone. First we carried out the analytical method development to achieve the analytical performance characteristics. Then we performed validation of the analytical method obtaining linearity, instrumental intra-assay and inter-assay precision, and accuracy and recovery percentage.ResultsChromatographic conditions were: flow rate 1.6 mL/min, 55% acetonitrile and 45% phosphate buffer (adjusted to pH=10) as the mobile phase. Injection volume was 50 µL, the temperature in the column compartment was 40°C. The column used was the Xterra C18 because methadone pKa is 8.3. Retention time for methadone was 4.5 min and for parabens 1.5 min.The final methadone determination method was validated for a standard of 10 mg/mL and applied for the determination of methadone with two parabens. The most relevant results were: correlation coefficient r=0.9957 for methadone in the range tested (7.5–12.5 mg/mL); instrumental precision 0.33% for standards (n=10); intra-assay precision 0.53% (n=6) and inter-assay precision 1.95% (n=12). The relative standard deviation percentage for accuracy was 1.28%, and the percentage recovery was 101.5 ±1.5%.Conclusion and relevanceAnalytical method development and validation procedures are vital in the discovery and development of drugs and pharmaceuticals to ensure performance of the method. The proposed HPLC conditions to determine methadone were proved to be valid and reproducible for carrying out physicochemical stability studies of different methadone oral solutions.References and/or acknowledgementsNo conflict of interest.
A possible benefit has been suggested for early treatment of severe coronavirus disease 2019 (COVID-19) with remdesivir. The efficacy of this drug is controversial and could significantly influence ...the efficiency in healthcare systems. The objective is the methodological interpretation of subgroup analyzes according to starting of remdesivir treatment with respect to symptom onset of COVID-19.
A search in Pubmed® database was performed. Randomized clinical trials (RCTs) with subgroup analysis regarding early and late use of remdesivir were selected. All endpoints were assessed using two methodologies. First methodology considered statistical interaction, pre-specification, biological plausibility, and consistency of results. Second methodology was a validated tool with preliminary questions to discard subset analysis without relevant minimum conditions, and a checklist with recommendations for applicability.
A total of 54 results were found and five RCTs were selected. According first methodology, consistent heterogeneity was only found in time to clinical improvement and better clinical status score at day 15 for patients with severe COVID-19 and <7 days of symptoms. About second methodology, these results about early use of remdesivir may be applied to clinical practice with caution.
We developed a systematic search and application of an established methodology for interpretation of subgroup analysis about early use of remdesivir. Results in severe COVID-19 suggested that early use of remdesivir provides a greater benefit in <7 days of symptoms for time to clinical improvement and better clinical status score at day 15. Future studies could use 7-day cut-off of symptoms to evaluate remdesivir.
Background: The peach lipid transfer protein Pru p 3 has been identified as a major allergen from this fruit. Homologous cross-reactive allergens have been found in several plant foods and pollens. ...Recombinant Pru p 3 has been recently produced in the yeast Pichia pastoris . Objective: We sought to evaluate the potential role of recombinant Pru p 3 as a novel tool for the diagnosis of fruit allergy. Methods: Circular dichroism analysis was used to compare the protein folding of natural Pru p 3 and recombinant Pru p 3. IgE binding by both molecular forms was quantified by means of ELISA and ELISA inhibition assays, and their biologic activity was estimated by using basophil activation, histamine release, and sulphidoleukotriene production tests. Individual sera or blood samples from patients with peach allergy (up to 17) were used in the assays. Results: A nearly identical circular dichroism spectra was shown by using natural Pru p 3 and recombinant Pru p 3, indicating that both protein forms are similarly folded. No difference was detected in the IgE-binding capacity of the 2 mo-lecular versions. Basophil activation and induction of sulphidoleukotriene production were positive in 9 of 10 patients, and histamine release was induced in at least half of the patients, with similar effects of the natural and recombinant forms in the 3 assays. Conclusion: Recombinant Pru p 3 shows a strong immunologic activity equivalent to that of its natural counterpart, and therefore it can be a useful tool for diagnosis (and future immunotherapy) of fruit allergy. (J Allergy Clin Immunol 2003;111:628-33.)
PDF
