bluuebunny/crossref_metadata_2025 huggingface dataset:
Beyond Susceptible and Resistant, Part II: Treatment of Infections Due to Gram-Negative Organisms Producing Extended-Spectrum β-Lactamases
Authors: Curello Jennifer , MacDougall Conan
Published: October 2020

The production of β-lactamase is the most common mechanism of resistance to β-lactam antibiotics among gram-negative bacteria. Extended-spectrum β-lactamases (ESBLs) are capable of hydrolyzing most penicillins, extended-spectrum cephalosporins, and aztreonam, but their activity is suppressed in the presence of a β-lactamase inhibitor. Serious infections with ESBL-producing isolates are associated with high rates of mortality, making early detection and adequate medical management essential to ensure optimal patient outcomes. Much controversy has centered on the recommendations for testing and reporting of antibiotic susceptibility of potential ESBL-producing organisms. The latest version of the Clinical Laboratory Standards Institute (CLSI) susceptibility reporting guidelines, published in 2010, no longer advocates for phenotypic testing of ESBL-producing isolates. From newer studies demonstrating a correlation between organism minimum inhibitory concentration (MIC) and clinical outcome, along with pharmacokinetic/pharmacodynamic (PK/PD) modeling demonstrating the importance of the MIC to achieving therapeutic targets, the CLSI has assigned lower susceptibility breakpoints for aztreonam and most cephalosporins. The new guidelines recommend using the lower MIC breakpoints to direct antibiotic selection. This article reviews the microbiology and epidemiology of ESBLs, the recent change in CLSI susceptibility reporting guidelines for ESBLs, and the clinical and PK/PD data supporting the relationship between in vitro susceptibility and clinical outcome. Finally, considerations for antimicrobial selection when treating patients with infections caused by ESBL-producing organisms from various sources are discussed.
Usefulness of Defined Daily Dose and Days of Therapy in Pediatrics and Obstetrics-Gynecology: A Comparative Analysis of Antifungal Drugs (2000–2001, 2005–2006, and 2010–2011)
Authors: Guillot Justine , Lebel Denis , Roy Hélène , Ovetchkine Philippe , Bussières Jean-François
Published: October 2020

OBJECTIVES: The objective was to describe antifungal drug use by using the number of defined daily doses (DDD)/1000 patient-days per antifungal, the number of days of therapy (DOT)/1000 patient-days per antifungal, and the mean dose in mg/kg/day per antifungal during a 10-year period.

METHODS: Retrospective, cross-sectional, descriptive study, in a mother-child university hospital center, with 400 pediatric beds and 100 obstetrics-gynecology beds. All inpatients who received 1 of the 7 authorized antifungals on the institution’s local formulary in 2000–2001, 2005–2006, or 2010–2011 were included. Prescriptions for emergency department and outpatient clinics were excluded. The data were extracted from the patients’ computerized medication profiles linked to patient admission, discharge, and transfer data. The DDD, DOT, and the mean dose in mg/kg/day were calculated for each antifungal and overall.

RESULTS: There was a 2.97-fold increase in the overall number of DDD/1000 patient-days, from 14.8 in 2000–2001 to 37.5 in 2005–2006 and 43.9 in 2010–2011. There was a 2.97-fold increase in the overall number of DOT/1000 patient-days, from 22.8 in 2000–2001 to 50.3 in 2005–2006 and 67.8 in 2010–2011.

CONCLUSIONS: It can be difficult to compare the use of antifungal drugs among institutions, owing to numerous factors, but it gives an idea about the consumption outside the studied center. Moreover, these ratios help to evaluate the use of antifungals within a same institution. These data could be correlated among others, with resistance patterns, in order to improve our daily practice concerning antifungal prescription.
Cinacalcet Administration by Gastrostomy Tube in a Child Receiving Peritoneal Dialysis
Authors: Nichols Kristen R. , Knoderer Chad A. , Johnston Bethanne , Wilson Amy C.
Published: October 2020

A 2-year-old male with chronic kidney disease with secondary hyperparathyroidism developed hypercalcemia while receiving calcitriol, without achieving a serum parathyroid hormone concentration within the goal range. Cinacalcet 15 mg (1.2 mg/kg), crushed and administered via gastrostomy tube, was added to the patient’s therapy. This therapy was effective in achieving targeted laboratory parameters in our patient despite instructions in the prescribing information that cinacalcet should always be taken whole.
Developmental Pharmacokinetics in Pediatric Populations
Authors: Lu Hong , Rosenbaum Sara
Published: October 2020

Information on drug absorption and disposition in infants and children has increased considerably over the past 2 decades. However, the impact of specific age-related effects on pharmacokinetics, pharmacodynamics, and dose requirements remains poorly understood. Absorption can be affected by the differences in gastric pH and stomach emptying time that have been observed in the pediatric population. Low plasma protein concentrations and a higher body water composition can change drug distribution. Metabolic processes are often immature at birth, which can lead to a reduced clearance and a prolonged half-life for those drugs for which metabolism is a significant mechanism for elimination. Renal excretion is also reduced in neonates due to immature glomerular filtration, tubular secretion, and reabsorption. Limited data are available on the pharmacodynamic behavior of drugs in the pediatric population. Understanding these age effects provide a mechanistic way to identify initial doses for the pediatric population. The various factors that impact pharmacokinetics and pharmacodynamics mature towards adult values at different rates, thus requiring continual modification of drug dose regimens in neonates, infants, and children. In this paper, the age-related changes in drug absorption, distribution, metabolism, and elimination in infants and children are reviewed, and the age-related dosing regimens for this population are discussed.
Evaluation of Enoxaparin Dosing and Monitoring in Pediatric Patients at Children's Teaching Hospital
Authors: McCormick Elizabeth W. , Parbuoni Kristine A. , Huynh Donna , Morgan Jill A.
Published: October 2020

OBJECTIVES: The primary objective of this study was to evaluate whether empirical enoxaparin doses according to Chest guidelines resulted in therapeutic antifactor Xa concentrations in pediatric patients. Secondary objectives were to determine the median enoxaparin dose that resulted in therapeutic anticoagulation, the median time to therapeutic concentrations, and the percentage of patients who experienced major bleeding.

METHODS: Patients in a tertiary medical center who were <18 years of age and received treatment doses of enoxaparin between July 2007 and June 2010 were included. Patients with <2 antifactor Xa concentrations or with only supratherapeutic concentrations and doses that were higher than recommended by the guidelines were excluded. Subgroup analysis was conducted by dividing children into 4 age groups: <2 months of age, 2 months to <1 year of age, 1 year to <3 years of age, and 3 to 17 years of age.

RESULTS: Thirty-two patients were included in the study. Thirty-seven percent of the patients achieved a therapeutic drug level with empirical dosing. The therapeutic dose ranged from 1 to 1.9 mg/kg in patients <1 year old, and 0.6 to 1.5 mg/kg in those =1 year of age. Comparison of the median therapeutic doses for patients 2 months to <1 year to that for patients =1 year old using the Mann-Whitney U test showed the median doses to be significantly difierent between the 2 groups (p=0.01). The antifactor Xa level became therapeutic on day 5 (median). There were no major bleeding events.

CONCLUSION: Less than 40% of patients were therapeutic with empirical dosing, which supports findings from other studies that suggest a need for modification of empirical treatment dosing of enoxaparin in children.
Injectable Dexamethasone Sodium Phosphate Administered Orally? A Pharmacokinetic Analysis of a Common Emergency Department Practice
Authors: Toledo Alexander , Amato Christopher S. , Clarke Nigel , Reitz Richard E. , Salo David
Published: October 2020

BACKGROUND: The injectable formulation of dexamethasone has been administered orally, for the treatment of pediatric asthma and croup. The practice is followed in emergency departments around the country, but pharmacokinetic data supporting this practice are lacking.

OBJECTIVES: This study evaluated the relative bioavailability and pharmacokinetics of dexamethasone sodium phosphate for injection (DSPI) administered orally compared to dexamethasone oral concentrate (DOC) in healthy adults.

METHODS: This was an open label, crossover study of 11 healthy adults 18 to 45 years of age. All subjects received 8 mg of dexamethasone oral concentrate initially. After a 1-week wash-out period, subjects received 8 mg of DSPI administered orally. Dexamethasone levels were measured by liquid chromatography in tandem mass spectrometry. Cmax and area under the curve (AUC (0-t) and AUC (0-∞)) were calculated and compared between groups using the paired t test.

RESULTS: The mean ± SD AUC(0-t) for dexamethasone oral concentrate and DSPI were 5497.23 ± 1649 and 4807.82 ± 1971) ng/dL/hr, respectively; 90% confidence interval (CI) was 78.8%–96.9%. The mean ± SD AUC(0-∞) for dexamethasone oral concentrate and DSPI were 6136.43 ± 2577 and 5591.48 ± 3075 ng/dL/hr, respectively; 90% CI was 79.0% –105.2%. Mean Cmax ± SD for DOC and DSPI were 942.94 ± 151 and 790.92 ± 229 ng/dL, respectively; 90% CI 76.8%–91.7%. The relative bioavailability of DSPI administered orally was 87.4% when using AUC(0-t) and 91.1% when using AUC(0-∞). The calculated absolute bioavailability was 75.9%.

CONCLUSIONS: DSPI is not bioequivalent to dexamethasone oral concentrate when administered orally. The existing literature supports the efficacy of DSPI despite this. Dosing adjustments may be considered.
Extended-Interval Gentamicin Dosing in Achieving Therapeutic Concentrations in Malaysian Neonates
Authors: Low Yee Shan , Tan Sin Li , Wan Angeline SL
Published: October 2020

OBJECTIVE: To evaluate the usefulness of extended-interval gentamicin dosing practiced in neonatal intensive care unit (NICU) and special care nursery (SCN) of a Malaysian hospital.

METHODS: Cross-sectional observational study with pharmacokinetic analysis of all patients aged ≤28 days who received gentamicin treatment in NICU/SCN. Subjects received dosing according to a regimen modified from an Australian-based pediatric guideline. During a study period of 3 months, subjects were evaluated for gestational age, body weight, serum creatinine concentration, gentamicin dose/interval, serum peak and trough concentrations, and pharmacokinetic parameters. Descriptive percentages were used to determine the overall dosing accuracy, while analysis of variance (ANOVA) was conducted to compare the accuracy rates among different gestational ages. Pharmacokinetic profile among different gestational age and body weight groups were compared by using ANOVA.

RESULTS: Of the 113 subjects included, 82.3% (n = 93) achieved therapeutic concentrations at the first drug-monitoring assessment. There was no significant difference found between the percentage of term neonates who achieved therapeutic concentrations and the premature group (87.1% vs. 74.4%), p = 0.085. A total of 112 subjects (99.1%) achieved desired therapeutic trough concentration of <2 mg/L. Mean gentamicin peak concentration was 8.52 mg/L (95% confidence interval [Cl], 8.13–8.90 mg/L) and trough concentration was 0.54 mg/L (95% CI, 0.48–0.60 mg/L). Mean volume of distribution, half-life, and elimination rate were 0.65 L/kg (95% CI, 0.62–0.68 L/kg), 6.96 hours (95% CI, 6.52–7.40 hours), and 0.11 hour−1 (95% CI, 0.10–0.11 hour−1), respectively.

CONCLUSION: The larger percentage of subjects attaining therapeutic range with extended-interval gentamicin dosing suggests that this regimen is appropriate and can be safely used among Malaysian neonates.
Reported Rates of Diarrhea Following Oral Penicillin Therapy in Pediatric Clinical Trials
Authors: Kuehn Jemima , Ismael Zareen , Long Paul F. , Barker Charlotte I.S. , Sharland Mike
Published: October 2020

OBJECTIVES: Antibiotic-associated diarrhea (AAD) is a well-recognized adverse reaction to oral penicillins. This review analyzed the literature to determine the incidence of AAD following amoxicillin, amoxicillin/clavulanate, and penicillin V oral therapy in pediatric clinical trials.

METHODS: An advanced search was conducted in MEDLINE and Embase databases for articles in any language reporting the incidence of AAD following oral penicillin therapy for any indicated infection in children (0–17 years). The search was limited to clinical trials. Articles were excluded if treatment was related to chronic conditions, involved concomitant antimicrobials, or if the dose or number of patients was not specified.

RESULTS: Four hundred thirty-five articles relating to clinical trials were identified (307 from Embase; 128 from MEDLINE). Thirty-five articles reporting on 42 studies were included for analysis. The indications included acute otitis media, sinusitis, pharyngitis, and pneumonia. Thirty-three trials reported on amoxicillin/clavulanate, 6 on amoxicillin, and 3 on penicillin V. In total, the 42 trials included 7729 children who were treated with an oral penicillin. On average, 17.2% had AAD. Data were pooled for each penicillin. The AAD incidence was 19.8% for amoxicillin/clavulanate, 8.1% for amoxicillin, and 1.2% for penicillin V. The amoxicillin/clavulanate data were analyzed according to formulation: pooled-average. The incidence of ADD was 24.6% for the 4:1 formulation, 12.8% for the 7:1 formulation, 19.0% for the 8:1 formulation, and 20.2% for the 14:1 formulation.

CONCLUSIONS: These results demonstrate substantially increased incidence of AAD following use of amoxicillin/clavulanate, compared to use of amoxicillin and penicillin V, as well as varying AAD rates with diffierent amoxicillin/clavulanate formulations. These findings warrant consideration when prescribing. The underlying mechanisms of AAD in children remain unclear.
Patterns of Off-Label Prescribing in the Pediatric Intensive Care Unit and Prioritizing Future Research
Authors: Czaja Angela S. , Reiter Pamela D. , Schultz M. Lynn , Valuck Robert J.
Published: October 2020

OBJECTIVES: To characterize off-label prescribing among US pediatric intensive care units (PICUs), determine characteristics associated with off-label use, and identify medications in highest need for additional study.

METHODS: Medications prescribed for ≥1% PICU patients (age < 18 years) in 2010 were identified from 39 children's hospitals. Use in a patient younger than the Food and Drug Administration (FDA)-approved age for any indication was considered off-label. Hierarchical multivariable modeling was used to identify characteristics associated with off-label use, accounting for center effects. Highest-impact drugs were defined by: 1) high off-label use (off-label use in at least 5% of the PICU cohort), 2) high risk medication, and 3) high priority status by the FDA or Best Pharmaceuticals for Children Act (BPCA).

RESULTS: A total of 66,896 patients received ≥1 medication of interest (n = 162) during their PICU stay. A median of 3 (interquartile range, 2–6) unique drugs per patient were used off-label. Those who received ≥1 drug off-label (85% of the cohort) had longer median PICU (2 days vs 1 day) and hospital (6 days vs 3 days) lengths of stay and higher mortality (3.6% vs 0.7%), p < 0.001. Factors independently associated with off-label drug use included: age 1 to 5 years, chronic conditions, acute organ failures, mechanical ventilation, arterial or venous catheters, dialysis, and blood products. Half of prescribed medications (n = 84) had been used off-label: 26 with significant off-label use, 30 high-risk medications, and 47 with high FDA/BPCA priority. The highest impact medications identified were: dexmedetomidine, dopamine, hydromorphone, ketamine, lorazepam, methadone, milrinone, and oxycodone.

CONCLUSIONS: Most PICU patients are exposed to off-label medication use, with uncertain evidence. Future medication research in this population should focus on medications with high impact potential.
Premixed Parenteral Nutrition Solution Use in Children
Authors: Chhim Rebecca F. , Crill Catherine M.
Published: October 2020

OBJECTIVES: In response to national drug shortages, our institution established criteria for the use of commercial premixed parenteral nutrition (PN) solutions in select pediatric patients. Although these solutions have been marketed for use in children, there are no data in this patient population. The objective of this study was to review our use of commercial premixed PN solutions in children.

METHODS: This was a retrospective review of patients ≤18 years of age who received a premixed PN solution from October 2010 to April 2012. All premixed PN courses were assessed for incidence of premixed PN discontinuation due to laboratory abnormalities. Estimated goal and actual protein and total caloric intake were evaluated for premixed PN courses that were continued for >48 hours.

RESULTS: Sixty-nine patients received 74 courses of premixed PN solutions for a mean duration of 5.6 ± 6.2 (range, 1–31) days. Fifteen courses (20%) required discontinuation of premixed PN as a result of mild laboratory abnormalities. No changes in clinical status were observed in patients and all abnormalities were corrected after switching to individualized PN. In patients receiving PN for >48 hours, premixed PN solutions provided goal protein in 48/49 (98%) courses and goal calories in 33/49 (67%) courses.

CONCLUSIONS: Premixed PN solutions were used in a wide range of pediatric patients and provide a potential option for PN support in pediatric patients when drug shortages limit PN product supply. Close monitoring for electrolyte abnormalities and protein and caloric intake is recommended when using premixed PN solutions in children.
Novel Use of Tolvaptan in a Pediatric Patient With Congestive Heart Failure Due to Duchenne Muscular Dystrophy and Congenital Adrenal Hyperplasia
Authors: Sami Sarah A. , Moffett Brady S. , Karlsten Melissa L. , Cabrera Antonio G. , Price Jack F. , Dreyer William J. , Denfield Susan W. , Jeewa Aamir
Published: October 2020

Successful management of hyponatremia in heart failure patients requires a multifaceted approach in order to preserve end-organ function. We describe the novel use of a selective vasopressin receptor antagonist, tolvaptan, for management of hyponatremia in a 17-year-old Caucasian male with severe Duchenne muscular dystrophy, congestive heart failure (CHF), and congenital adrenal hyperplasia. The medical history was significant for recurrent admissions for hyponatremia secondary to adrenal crises, which was also exacerbated by his CHF. After initiation of tolvaptan and its extended administration, he had no further hyponatremia-related admissions and no adverse reactions. The complexity of this combination of conditions is presented, and the efficacy of the drug and the rationale behind the treatment approach is discussed.
Mathematical modelling of primary and secondary pyrolysis: State of the art
Authors: Trninić Marta
Published: October 2020

Pyrolysis process converts biomass into liquid, gaseous and solid fuels. Chemical kinetics play a key role in explaining the characteristics of pyrolysis reactions and developing mathematical models. Many studies have been undertaken to understand the kinetics of biomass pyrolysis; however, due to the heterogeneity of biomass and the complexity of the chemical and physical changes that occur during pyrolysis, it is difficult to develop a simple kinetic model that is applicable in every case. In this review, different methods to describe biomass primary and secondary pyrolysis with different types of kinetic mechanisms are discussed.
Convergence of transonic wind tunnel test results of the AGARD-B standard model
Authors: Damljanović Dijana , Vuković Đorđe , Ocokoljić Goran , Rašuo Boško
Published: October 2020

AGARD-B is a widely-used configuration of a standard wind tunnel model. Beside its originally intended application for correlation of data from supersonic wind tunnel facilities, it was tested in a wide range of Mach numbers and, more recently, used for assessment of wall interference effects, validation of computational fluid dynamics codes and validation of new model production technologies. The researchers and wind tunnel test engineers would, naturally, like to know the "true" aerodynamic characteristics of this model, for comparison with their own work. Obviously, such data do not exist, but an estimate can be made of the dispersion of test results from various sources and of the probable "mean" values of the aerodynamic coefficients. To this end, comparable transonic test results for the AGARD-B model at Mach numbers 0.77, Mach 1.0 and Mach 1.17 from six wind tunnels were analyzed and average values and dispersions of the aerodynamic coefficients were computed.
Bio-inspired approach for innovative design of knee protectors for recreational sports
Authors: Zdravkova Ana , Mircheski Ile , Sidorenko Sofija
Published: October 2020

In this paper the process of an innovative design of a knee protector is presented. The main goal of the research was to find a creative design solution for more efficient protective equipment for light recreational sports. The research is based on an interdisciplinary approach where the possibilities of ergonomics and bionics methods were applied. In order to recognize and provide proper design requirements a valuable market research in the field of knee protector products was performed. An ergonomic research was implemented with intention to define the detailed requirements for more comfort, better functioning and better protection from injuries. The design process was completed following the problem-driven bio-inspiration approach. The armadillo's shell structure, consisted of tiles connected with collagen fibers, was an inspiration for an innovative design approach. The result is a virtual 3D model of an innovative design of a knee protector, with intention to be further developed and tested as a 3D printed prototype, until achieving the phase of final product.
Mixing enhancement of wheat granules in a hopper bottom lab-scale mixer using discrete element simulations
Authors: Garneoui Seifeddine , Keppler István , Korzenszky Péter
Published: October 2020

In the agricultural industry, the conservation of wheat grains in silos after stocking is a hard task. This is because when stocking a large crop, hot aeration from the bottom of the silo is not sufficient to preserve the crop and avoid losses due to the manifestation of moisture between grains and grains-wall. As a concern, engineers, as well as inspectors, challenged day-to-day issues whenever packing such granular material. A screw could be a good solution to improve the dryness of the particles and mix the bed material in case of stocking different types of grains. Mainly, the complexity does emanate from the model used to predict accurately the mixing performance. Emerging generation of simulation codes using the discrete element method (e.g., EDEM®, LIGGGHTS, etc.) have brought an intact solution to the problem of particulate flow and particles inhomogeneity. The present work has sought to develop predictive models for average mixing index and particles velocity distribution assessments in mixing of wheat granules in a small-scaled hopper base screw mixer. A screw-mated-horizontal-ploughs has been utilized to improve the agitation of grains rather than a simple screw. 1, 2 and 4 mated ploughs to the screw axle has been used, also the tilt angle of the 4 mated ploughs case has been varied as follows; 20°, 45° and 70° then evaluated. Next, findings regarding bed homogeneity are calculated using the Lacey method [1] for quantitative analysis and visual observations have been read out for qualitative assessment. Particles inhomogeneity is at its minimum when more ploughs mated to the screw were used.
Numerical modeling of Nomex honeycomb core composite plates at meso scale level
Authors: Dinulović Mirko , Rašuo Boško , Trninić Marta , Adžić Vuk
Published: October 2020

Honeycomb core composite plates are becoming more important in the construction of primary aerospace structures. Nowadays, these types of materials are used for construction of fuselage skins, central and outer wing boxes, engine tail cones, landing gear doors, command surfaces like spoilers and ailerons etc. To determine the stress strain field in loaded honeycomb plates elastic coefficients are required. In the present work, a method for determining all required elastic coefficients for the core and plates is presented. Using experimentally obtained values for Nomex paper (type 410) and phenolic resin material model is presented and FEA model of composite plate with honeycomb core is created and three point bend test is simulated. Numerically obtained stress and strain values are compared to the experiment. Good agreement between proposed material model and experimentally obtained values is observed.
Advance in ultrasonic spray pyrolysis (USP) for the synthesis of gold nanoparticles
Authors: Stopić Srećko , Fridrih Bernd
Published: October 2020

Introduction/purpose: Ultrasonic spray pyrolysis (USP) is usually used for the preparation of submicronic and nanosized gold powders. This is a simple method for a synthesis from an aerosol containing dissolved metallic salts such as gold chloride, gold nitrate, and gold-acetate, obtained in the ultrasonic field using frequencies ranging from 0.8 to 2.5 MHz. Methods: The USP method combines aerosol formation in an ultrasonic field, transport of an aerosol with a carrier gas to the reactor and final reduction of HAuCl4 with a used gas such as hydrogen and carbon monoxide. The thermal decomposition of gold acetate takes place in a neutral atmosphere such as nitrogen and argon at elevated temperatures. The chemical reduction of HAuCl4 takes place in the aqueous phase using sodium citrate and sodium boride after heating water solution. Results: Powders of gold were obtained at room temperature using hydrogen reduction in an ultrasonic field at room temperature from HAuCl4 using a frequency of 0.8 MHz. The obtained gold particles were analysed using scanning electron microscopy (SEM) and energy disperse spectroscopy (EDS). The formed particles are round and agglomerated. An increase in temperature to 260°C and 500°C leads to the formation of spherical and cylindrical gold particles. Conclusion: New improved equipment for an ultrasonic spray pyrolysis synthesis of gold powder from HAuCl4 with hydrogen reduction was offered by PRIZMA, Kragujevac, Serbia, enabling a controlled reduction process with better prevention of piezo transducers in an ultrasonic field and increased aerosol production and its transport to the reaction furnace.
Zeta function and some of its properties
Authors: Fabiano Nikola
Published: October 2020

Introduction/purpose: Some properties of the zeta function will be shown as well as its applications in calculus, in particular the "golden nugget formula" for the value of the infinite sum 1 + 2 + 3 + · · · . Some applications in physics will also be mentioned. Methods: Complex plane integrations and properties of the Gamma function will be used from the definition of the function to its analytic extension. Results: From the original definition of the z(s) function valid for s > 1 a meromorphic function is obtained on the whole complex plane with a simple pole in s = 1. Conclusion: The relevance of the zeta function cannot be overstated, ranging from the infinite series to the number theory, regularization in theoretical physics, the Casimir force, and many other fields.
Revisiting the Pylos Episode and Thucydides' 'Bias' against Cleon
Authors: Nikolaidis Anastasios
Published: October 2020

The Pylos episode, ending with the capture of almost 300 Spartans who had been cut off on the Sphacteria island, was the first major setback suffered by Sparta during the Peloponnesian war and, at the same time, the first major – and more importantly – unexpected success of Athens, in Peloponnesian territory at that. Without overlooking the military side involved, this paper will primarily focus on the political aspects of this enterprise in an attempt (a) to assess and evaluate Thucydides’ attitude to the protagonists of this episode, Cleon, Nicias and Demosthenes, (b) to better understand the historian’s political stance and judgement through the vocabulary that he employs, and (c) to show that his notoriously presumed bias against Cleon is poorly substantiated and, insofar as it may occasionally occur, it does not interfere with his respect for historical truth.
Grænsearbejde blandt grænsependlere
Authors: Andersen Dorte Jagetic , Winkler Ingo
Published: October 2020

Inspireret af Chris Rumfords teori om grænsearbejde fokuserer artiklen på måden, hvorpå den dansk-tyske grænse praktiseres og derigennem udleves af grænsependlere, der bor og arbejder på forskellige sider af den. I vores etnografiske studier har det vist sig, at måden, grænsependlere praktiserer og lever med grænser i deres hverdag på, udtrykker en mangfoldighed af grænser, der er i konstant dialog i pendlernes hverdagsliv. Særligt betydningen af mobilitet og det at være mobil, og af bevægelse mere generelt, er et væsentligt fundament for at udleve grænsen, men også nationale forskelle og identitetsdannelse og ikke mindst sproglig praksis danner grundlag for særlige måder at udleve grænser på. Det er vores indtryk at grænser og deres konsekvenser først forstås i lyset af den praksis, i hvilken de virkeliggøres, og at denne praksis aldrig er entydigt geopolitisk determineret, men nærmere åbner op for en konstant forhandling af, hvad grænser er.
Interview med Jens Andresen: Grænseoverskridende samarbejde i den dansk-tyske grænseregion
Authors: Frandsen Steen Bo
Published: October 2020

Jens Andresen har altid haft grænsen tæt inde på livet. Han er født og opvokset i en dansksindet familie lige syd for 1920-grænsen og vendte efter sin uddannelse på Landbohøjskolen i København tilbage til grænseregionen. Hanblev dog på den danske side af grænsen og engagerede sig politisk i amts- ogsiden regionsrådet. I de seneste år har han været formand for Grænseforeningen. En position, som han nu forlader.
”Hacking” – forbrydelse eller digitalt selvforsvar?
Authors: Lentz Lene Wacher , Pedersen Jens Myrup
Published: October 2020

Vi kender først og fremmest ”hacking” som en forbrydelse. De større, opsigtsvækkende ”hacking”-angreb hører vi om i nyhederne. Dog bliver ”hacking”-metoden nu også italesat som en it-sikkerheds-kompetence. Således udbydes flere steder kurser i ”hacking”, og Forsvarets Efterretningstjeneste har oprettet et ”Hackerakademi” for at rekruttere talenter til statens tjeneste. Begrebet ”hacking” kan skabe forvirring, for alt er ikke tilladt for at optimere eller teste sikkerheden ved it-systemer. Denne artikel klarlægger, hvornår der straffes for ”hacking” efter straffeloven. Desuden undersøges, om en it-sikkerhedsaktør må bruge ”hacking” som et forsvar, når it-systemer bliver angrebet af en fjendtlig ”hacker”. I artiklen illustreres, at det kan være vanskeligt at forudsige, hvor grænserne for strafansvar går for den, der vil optimere sikkerheden ved sine systemer.
Det internationale Folketing og muligheden for diplomatisk koordination
Authors: Lassen Viktor Lerche-Jørgensen
Published: October 2020

Som så mange andre parlamenter har Folketinget gjort sig bemærket som en aktiv international aktør. Selvom udenrigspolitik formelt er et regeringsanliggende, er kontakten til udlandet en fast del af arbejdet i Folketingets udvalg, delegationer, partier og Præsidium. Dette “parlamentariske diplomati” opererer til tider uafhængigt af, men oftest i koordination med Udenrigsministeriet, der bl.a. bistår i planlægningen af udvalgsrejser. I denne kronik diskuteres, hvorvidt et mere strategisk samarbejde kan føre til en bedre udnyttelse af den diplomatiske kapacitet. Historien viser, at samarbejde mellem det ministerielle og det parlamentariske diplomati kan fungere godt, men at en balancegang kræves for at sikre, at hverken Folketingets autonomi eller regeringens udenrigspolitiske prærogativ sættes over styr. Tilrettelægges det ordentligt, kan et samarbejde dog være fordelagtigt for såvel Folketinget som for regeringen og Udenrigsministeriet.
An International Standardized Magnetic Resonance Imaging Protocol for Diagnosis and Follow-up of Patients with Multiple Sclerosis
Authors: Saslow Lori , Li David K.B. , Halper June , Banwell Brenda , Barkhof Frederik , Barlow Laura , Costello Kathleen , Damiri Peter , Dunn Jeffrey , Giri Shivraman , Maes Micki , Morrow Sarah A. , Newsome Scott D. , Oh Jiwon , Paul Friedemann , Quarterman Patrick , Reich Daniel S. , Shewchuk Jason R. , Shinohara Russell Takeshi , Van Hecke Wim , van de Ven Kim , Wallin Mitchell T. , Wolinsky Jerry S. , Traboulsee Anthony
Published: October 2020

Standardized magnetic resonance imaging (MRI) protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS). The Consortium of Multiple Sclerosis Centers (CMSC) convened an international panel of MRI experts to review and update the current guidelines. The objective was to update the standardized MRI protocol and clinical guidelines for diagnosis and follow-up of MS and develop strategies for advocacy, dissemination, and implementation. Conference attendees included neurologists, radiologists, technologists, and imaging scientists with expertise in MS. Representatives from the CMSC, Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, US Department of Veteran Affairs, National Multiple Sclerosis Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis companies were present. Before the meeting, CMSC members were surveyed about standardized MRI protocols, gadolinium use, need for diffusion-weighted imaging, and the central vein sign. The panel worked to make the CMSC and MAGNIMS MRI protocols similar so that the updated guidelines could ultimately be accepted by international consensus. Advocacy efforts will promote the importance of standardized MS MRI protocols. Dissemination will include publications, meeting abstracts, educational programming, webinars, “meet the expert” teleconferences, and examination cards. Implementation will require comprehensive and coordinated efforts to make the protocol easy to access and use. The ultimate vision, and goal, is for the guidelines to be universally useful, usable, and used as the standard of care for patients with MS.
Bayesian inference for biophysical neuron models enables stimulus optimization for retinal neuroprosthetics
Authors: Oesterle Jonathan , Behrens Christian , Schröder Cornelius , Hermann Thoralf , Euler Thomas , Franke Katrin , Smith Robert G , Zeck Günther , Berens Philipp
Published: October 2020

While multicompartment models have long been used to study the biophysics of neurons, it is still challenging to infer the parameters of such models from data including uncertainty estimates. Here, we performed Bayesian inference for the parameters of detailed neuron models of a photoreceptor and an OFF- and an ON-cone bipolar cell from the mouse retina based on two-photon imaging data. We obtained multivariate posterior distributions specifying plausible parameter ranges consistent with the data and allowing to identify parameters poorly constrained by the data. To demonstrate the potential of such mechanistic data-driven neuron models, we created a simulation environment for external electrical stimulation of the retina and optimized stimulus waveforms to target OFF- and ON-cone bipolar cells, a current major problem of retinal neuroprosthetics.
The wtf4 meiotic driver utilizes controlled protein aggregation to generate selective cell death
Authors: Nuckolls Nicole L , Mok Anthony C , Lange Jeffrey J , Yi Kexi , Kandola Tejbir S , Hunn Andrew M , McCroskey Scott , Snyder Julia L , Bravo Núñez María Angélica , McClain Melainia , McKinney Sean A , Wood Christopher , Halfmann Randal , Zanders Sarah E
Published: October 2020

Meiotic drivers are parasitic loci that force their own transmission into greater than half of the offspring of a heterozygote. Many drivers have been identified, but their molecular mechanisms are largely unknown. Thewtf4gene is a meiotic driver inSchizosaccharomyces pombethat uses a poison-antidote mechanism to selectively kill meiotic products (spores) that do not inheritwtf4. Here, we show that the Wtf4 proteins can function outside of gametogenesis and in a distantly related species,Saccharomyces cerevisiae. The Wtf4poisonprotein forms dispersed, toxic aggregates. The Wtf4antidotecan co-assemble with the Wtf4poisonand promote its trafficking to vacuoles. We show that neutralization of the Wtf4poisonrequires both co-assembly with the Wtf4antidoteand aggregate trafficking, as mutations that disrupt either of these processes result in cell death in the presence of the Wtf4 proteins. This work reveals thatwtfparasites can exploit protein aggregate management pathways to selectively destroy spores.
The structures of secretory and dimeric immunoglobulin A
Authors: Kumar Bharathkar Sonya , Parker Benjamin W , Malyutin Andrey G , Haloi Nandan , Huey-Tubman Kathryn E , Tajkhorshid Emad , Stadtmueller Beth M
Published: October 2020

Secretory (S) Immunoglobulin (Ig) A is the predominant mucosal antibody, which binds pathogens and commensal microbes. SIgA is a polymeric antibody, typically containing two copies of IgA that assemble with one joining-chain (JC) to form dimeric (d) IgA that is bound by the polymeric Ig-receptor ectodomain, called secretory component (SC). Here, we report the cryo-electron microscopy structures of murine SIgA and dIgA. Structures reveal two IgAs conjoined through four heavy-chain tailpieces and the JC that together form a β-sandwich-like fold. The two IgAs are bent and tilted with respect to each other, forming distinct concave and convex surfaces. In SIgA, SC is bound to one face, asymmetrically contacting both IgAs and JC. The bent and tilted arrangement of complex components limits the possible positions of both sets of antigen-binding fragments (Fabs) and preserves steric accessibility to receptor-binding sites, likely influencing antigen binding and effector functions.
Distinct hierarchical alterations of intrinsic neural timescales account for different manifestations of psychosis
Authors: Wengler Kenneth , Goldberg Andrew T , Chahine George , Horga Guillermo
Published: October 2020

Hierarchical perceptual-inference models of psychosis may provide a holistic framework for understanding psychosis in schizophrenia including heterogeneity in clinical presentations. Particularly, hypothesized alterations at distinct levels of the perceptual-inference hierarchy may explain why hallucinations and delusions tend to cluster together yet sometimes manifest in isolation. To test this, we used a recently developed resting-state fMRI measure of intrinsic neural timescale (INT), which reflects the time window of neural integration and captures hierarchical brain gradients. In analyses examining extended sensory hierarchies that we first validated, we found distinct hierarchical INT alterations for hallucinations versus delusions in the auditory and somatosensory systems, thus providing support for hierarchical perceptual-inference models of psychosis. Simulations using a large-scale biophysical model suggested local elevations of excitation-inhibition ratio at different hierarchical levels as a potential mechanism. More generally, our work highlights the robustness and utility of INT for studying hierarchical processes relevant to basic and clinical neuroscience.
A new role for histone demethylases in the maintenance of plant genome integrity
Authors: Antunez-Sanchez Javier , Naish Matthew , Ramirez-Prado Juan Sebastian , Ohno Sho , Huang Ying , Dawson Alexander , Opassathian Korawit , Manza-Mianza Deborah , Ariel Federico , Raynaud Cecile , Wibowo Anjar , Daron Josquin , Ueda Minako , Latrasse David , Slotkin R Keith , Weigel Detlef , Benhamed Moussa , Gutierrez-Marcos Jose
Published: October 2020

Histone modifications deposited by the Polycomb repressive complex 2 (PRC2) play a critical role in the control of growth, development, and adaptation to environmental fluctuations of most multicellular eukaryotes. The catalytic activity of PRC2 is counteracted by Jumonji-type (JMJ) histone demethylases, which shapes the genomic distribution of H3K27me3. Here, we show that two JMJ histone demethylases in Arabidopsis, EARLY FLOWERING 6 (ELF6) and RELATIVE OF EARLY FLOWERING 6 (REF6), play distinct roles in H3K27me3 and H3K27me1 homeostasis. We show that failure to reset these chromatin marks during sexual reproduction results in the transgenerational inheritance of histone marks, which cause a loss of DNA methylation at heterochromatic loci and transposon activation. Thus, Jumonji-type histone demethylases play a dual role in plants by helping to maintain transcriptional states through development and safeguard genome integrity during sexual reproduction.
Sex-based differences in clearance of chronic Plasmodium falciparum infection
Authors: Briggs Jessica , Teyssier Noam , Nankabirwa Joaniter I , Rek John , Jagannathan Prasanna , Arinaitwe Emmanuel , Bousema Teun , Drakeley Chris , Murray Margaret , Crawford Emily , Hathaway Nicholas , Staedke Sarah G , Smith David , Rosenthal Phillip J , Kamya Moses , Dorsey Grant , Rodriguez-Barraquer Isabel , Greenhouse Bryan
Published: October 2020

Multiple studies have reported a male bias in incidence and/or prevalence of malaria infection in males compared to females. To test the hypothesis that sex-based differences in host-parasite interactions affect the epidemiology of malaria, we intensively followed Plasmodium falciparum infections in a cohort in a malaria endemic area of eastern Uganda and estimated both force of infection (FOI) and rate of clearance using amplicon deep-sequencing. We found no evidence of differences in behavioral risk factors, incidence of malaria, or FOI by sex. In contrast, females cleared asymptomatic infections at a faster rate than males (hazard ratio [HR]=1.82, 95% CI 1.20 to 2.75 by clone and HR = 2.07, 95% CI 1.24 to 3.47 by infection event) in multivariate models adjusted for age, timing of infection onset, and parasite density. These findings implicate biological sex-based differences as an important factor in the host response to this globally important pathogen.
Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes
Authors: Yi Danielle , Nguyen Hai P , Dinh Jennie , Viscarra Jose A , Xie Ying , Lin Frances , Zhu Madeleine , Dempersmier Jon M , Wang Yuhui , Sul Hei Sook
Published: October 2020

Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical energy into heat, thereby increasing energy expenditure. Here, we identify Dot1l, the only known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally activates the Ucp1 promoter and other BAT genes. Through a direct interaction, Dot1l is recruited by Zc3h10 to the promoter regions of thermogenic genes to function as a coactivator by methylating H3K79. We also show that Dot1l is induced during brown fat cell differentiation and by cold exposure and that Dot1l and its H3K79 methyltransferase activity is required for thermogenic gene program. Furthermore, we demonstrate that Dot1l ablation in mice using Ucp1-Cre prevents activation of Ucp1 and other target genes to reduce thermogenic capacity and energy expenditure, promoting adiposity. Hence, Dot1l plays a critical role in the thermogenic program and may present as a future target for obesity therapeutics.
The Use of Osteopathic Manipulative Medicine in the Management of Recurrent Mastitis
Authors: Jackson Caitlin , Loveless Brian
Published: October 2020

Mastitis affects breastfeeding mothers everywhere and management obstacles often lead to cessation of breastfeeding. Breastfeeding mastitis is commonly managed with antibiotics despite lack of clear infectious etiology. With the emerging problem of antibiotic resistance, novel managements are required. We present the case of a 34-year-old woman with 6 pregnancies and 3 children (gravida 6, parity 3) who had 5 cases of mastitis within 6 months treated with multiple courses of antibiotics. The patient underwent with osteopathic manipulative treatment (OMT) to the affected breast over 2 sessions and was taught how to perform self-myofascial release. Techniques are shown in an accompanying Supplemental Video. As of this report, the patient had been symptom free for 1 year. Future research, including a clinical trial of OMT, is required to determine whether osteopathic physicians can effectively manage recurrent lactational mastitis.
Optimised biomolecular extraction for metagenomic analysis of microbial biofilms from high-mountain streams
Authors: Busi Susheel Bhanu , Pramateftaki Paraskevi , Brandani Jade , Fodelianakis Stilianos , Peter Hannes , Halder Rashi , Wilmes Paul , Battin Tom J.
Published: October 2020

Glacier-fed streams (GFS) are harsh ecosystems dominated by microbial life organized in benthic biofilms, yet the biodiversity and ecosystem functions provided by these communities remain under-appreciated. To better understand the microbial processes and communities contributing to GFS ecosystems, it is necessary to leverage high throughput sequencing. Low biomass and high inorganic particle load in GFS sediment samples may affect nucleic acid extraction efficiency using extraction methods tailored to other extreme environments such as deep-sea sediments. Here, we benchmarked the utility and efficacy of four extraction protocols, including an up-scaled phenol-chloroform protocol. We found that established protocols for comparable sample types consistently failed to yield sufficient high-quality DNA, delineating the extreme character of GFS. The methods differed in the success of downstream applications such as library preparation and sequencing. An adapted phenol-chloroform-based extraction method resulted in higher yields and better recovered the expected taxonomic profile and abundance of reconstructed genomes when compared to commercially-available methods. Affordable and straight-forward, this method consistently recapitulated the abundance and genomes of a mock community, including eukaryotes. Moreover, by increasing the amount of input sediment, the protocol is readily adjustable to the microbial load of the processed samples without compromising protocol efficiency. Our study provides a first systematic and extensive analysis of the different options for extraction of nucleic acids from glacier-fed streams for high-throughput sequencing applications, which may be applied to other extreme environments.