Time-Kill Kinetics and In Vitro Antifungal Susceptibility of Non-fumigatus Aspergillus Species Isolated from Patients with Ocular Mycoses

Aspergillus species can cause ocular morbidity and blindness, and thus, appropriate antifungal therapy is needed. We investigated the in vitro activity of itraconazole, voriconazole, posaconazole, caspofungin, anidulafungin, and amphotericin B against 14 Aspergillus isolates obtained from patients with ocular mycoses, using the CLSI reference broth microdilution methodology. In addition, time-kill assays were performed, exposing each isolate separately to 1-, 4-, and 16-fold concentrations above the minimum inhibitory concentration (MIC) of each antifungal agent. A sigmoid maximum-effect (Emax) model was used to fit the time-kill curve data. The drug effect was further evaluated by measuring an increase/decrease in the killing rate of the tested isolates. The MICs of amphotericin B, itraconazole, voriconazole, and posaconazole were 0.5–1.0, 1.0, 0.5–1.0, and 0.25 µg/ml for A. brasiliensis, A. niger, and A. tubingensis isolates, respectively, and 2.0–4.0, 0.5, 1.0 for A. flavus, and 0.12–0.25 µg/ml for A. nomius isolates, respectively. A. calidoustus had the highest MIC range for the azoles (4.0–16.0 µg/ml) among all isolates tested. The minimum effective concentrations of caspofungin and anidulafungin were ≤0.03–0.5 µg/ml and ≤0.03 µg/ml for all isolates, respectively. Posaconazole demonstrated maximal killing rates (Emax = 0.63 h−1, r2 = 0.71) against 14 ocular Aspergillus isolates, followed by amphotericin B (Emax = 0.39 h−1, r2 = 0.87), voriconazole (Emax = 0.35 h−1, r2 = 0.098), and itraconazole (Emax = 0.01 h−1, r2 = 0.98). Overall, the antifungal susceptibility of the non-fumigatusAspergillus isolates tested was species and antifungal agent dependent. Analysis of the kinetic growth assays, along with consideration of the killing rates, revealed that posaconazole was the most effective antifungal against all of the isolates

Safety and Feasibility of Long-term Intravenous Sodium Nitrite Infusion in Healthy Volunteers

BACKGROUND: Infusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion. METHODOLOGY: Healthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075) between July 2007 and August 2008. All subjects provided written consent to participate. Twelve subjects (5 males, 7 females; mean age, 38.8±9.2 years (range, 21-56 years)) were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 µg/kg/hr; maximal dose of 533.8 µg/kg/hr). Clinical, physiologic and laboratory data before, during and after infusion were analyzed. FINDINGS: The maximal tolerated dose for intravenous infusion of sodium nitrite was 267 µg/kg/hr. Dose limiting toxicity occurred at 446 µg/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg) and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S-nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood. CONCLUSION: Sodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov; NCT00103025

Global Perspectives on Task Shifting and Task Sharing in Neurosurgery.

BACKGROUND: Neurosurgical task shifting and task sharing (TS/S), delegating clinical care to non-neurosurgeons, is ongoing in many hospital systems in which neurosurgeons are scarce. Although TS/S can increase access to treatment, it remains highly controversial. This survey investigated perceptions of neurosurgical TS/S to elucidate whether it is a permissible temporary solution to the global workforce deficit. METHODS: The survey was distributed to a convenience sample of individuals providing neurosurgical care. A digital survey link was distributed through electronic mailing lists of continental neurosurgical societies and various collectives, conference announcements, and social media platforms (July 2018-January 2019). Data were analyzed by descriptive statistics and univariate regression of Likert Scale scores. RESULTS: Survey respondents represented 105 of 194 World Health Organization member countries (54.1%; 391 respondents, 162 from high-income countries and 229 from low- and middle-income countries [LMICs]). The most agreed on statement was that task sharing is preferred to task shifting. There was broad consensus that both task shifting and task sharing should require competency-based evaluation, standardized training endorsed by governing organizations, and maintenance of certification. When perspectives were stratified by income class, LMICs were significantly more likely to agree that task shifting is professionally disruptive to traditional training, task sharing should be a priority where human resources are scarce, and to call for additional TS/S regulation, such as certification and formal consultation with a neurosurgeon (in person or electronic/telemedicine). CONCLUSIONS: Both LMIC and high-income countries agreed that task sharing should be prioritized over task shifting and that additional recommendations and regulations could enhance care. These data invite future discussions on policy and training programs

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Different approaches of clients and consultants to contractors’ qualification and selection

Nowadays, clients are the dominant groups in almost all types of industries. However, the construction industry is unique and consultants, as representatives of clients, are very important figures in this industry as well. By presenting survey findings of 91 clients and 50 consultants, this study reveals clients’ and consultants’ differing expectations of contracting organisations during contractor qualification and selection. The study has clearly confirmed the fact that consultants’ perspectives are rather different and their contractors’ expectations of their clients vary very significantly from the clients themselves. Furthermore, significantly different results were found even among different types of consultants and different categories of clients. Moreover, this study showed that both clients and consultants had high willingness to continue working with the same contractor in possible future works assuming they are satisfied with the previous works. The criteria, which contribute to achieving full client and/or consultant satisfaction and hence lead to possible repetitive works are identified and the results showed the existence of significant difference between clients and consultants perspectives regarding this issue as well. The framework presented within this paper aims to help the contracting organisations to compare and recognise the different approaches and perceptions of both clients and consultants during contractor qualification and selection processes. The contracting organisations in the related sectors will be able to use the framework provided within this study to recognise the overall demand in a more complete and better manner and hence formulate or modify strategies accordingly. Skirtingas klientų ir konsultantų požiÅ«ris į rangovo kvalifikacijÄ… ir atrankÄ… Santrauka Å iandien užsakovai tampa svarbiausia grupe beveik visose pramonÄ—s Å¡akose. TaÄiau statybos pramonÄ— unikali tuo, kad joje svarbiu asmeniu laikomas dar ir konsultantas, kuris samdomas kaip užsakovo atstovas. Pateikti 91 kliento ir 50 užsakovų apklausos rezultatai, kurie parodÄ—, kaip skiriasi klientų ir užsakovų lÅ«kesÄiai dÄ—l rangovų kvalifikacijos ir atrankos. Tyrimas parodÄ—, kad konsultantų reikalavimai rangovams labai skiriasi nuo užsakovo reikalavimų, be to, skirtingi konsultantai ir užsakovai kelia skirtingus reikalavimus rangovams. Tyrimas parodÄ—, kad užsakovai ir klientai yra linkÄ™ tÄ™sti bendradarbiavimÄ… su tuo paÄiu rangovu tvirtindami, kad yra patenkinti jo ankstesniu darbu. Nustatyti kriterijai, kurių atitikimas lemia užsakovo ir(arba) konsultanto pasirinkimÄ… ir galimybÄ™ ateityje laimÄ—ti konkursus. Pateikta sistema leidžia konkursuose dalyvaujanÄioms įmonÄ—ms suvokti ir palyginti užsakovų ir konsultantų reikalavimus rangovo atrankos metu. Konkursuose dalyvaujanÄios įmonÄ—s gali naudoti tyrimo rezultatus tam, kad suvoktų užsakovo poreikius, atitinkamai suformuluotų ir pritaikytų savo strategijas. ReikÅ¡miniai žodžiai: rangovo kvalifikacija, rangovo atranka, užsakovo lÅ«kesÄiai, konsultanto lÅ«kesÄiai, užsakovo poreikių patenkinimas, pasikartojantys darbai First Published Online: 14 Oct 201

Assessment and improvement of elementary force computations for cold forward rod extrusion

Two commonly used analytical force computation methods for cold forward rod extrusion are evaluated by means of precise finite element computations. The upperbound model by Avitzur based on the spherical velocity field and the model by Siebel based on a quasi-upper-bound solution are considered. It has been found that the pure deformation forces obtained by summing the ideal force and shear force terms deviate between +25% and -20% from the finite element solutions. Larger deviations, however, occur for the Coulomb-friction term in the container. A new model based on an elasto-static analysis combined with numerical analysis is suggested to compute this term. This new model supplies also the accurate pressure distribution within the container

Hamilton-Jacobi Modelling of Stellar Dynamics

Abstract One of the physical settings emerging in the galaxy and stellar dynamics is motion of a single star and a stellar cluster about a galaxy center. The potential availability of analytical treatment of this problem stems from the smallness of mass of the star and cluster relative to the galactic mass, giving rise to Hill&apos;s restricted three-body problem in the galaxy-cluster-star context. Based on this observation, this paper presents a Hamiltonian approach to modelling stellar motion by the derivation of canonical coordinates for the dynamics of a star relative to a star cluster. First, the Hamiltonian is partitioned into a linear term and a high-order term. The HamiltonJacobi equations are solved for the linear part by separation, and new constants for the relative motions are obtained, called epicyclic orbital elements. The effect of an arbitrary cluster potential is incorporated into the analysis by a variation of parameters procedure. A numerical optimization technique is developed based on the new orbital elements, and quasiperiodic stellar orbits are found