Cumulative Fraction Research Articles

Alcohol consumption, drinking patterns and cause-specific mortality in an Australian cohort of 181,607 participants aged 45 years and over.

Despite relatively high alcohol consumption in Australia, local evidence regarding drinking and cause-specific mortality is limited. We aimed to quantify the risk of alcohol-related causes of death and to calculate contemporary estimates of absolute risk and population attributable fractions for deaths caused by alcohol consumption in Australia. Prospective cohort study. Cox proportional hazards regressions were used to calculate hazard ratios (HR) for cause-specific mortality in relation to overall alcohol consumption and pattern of drinking among 181,607 of 267,357 participants aged ≥45 years (2005-2009) in the New South Wales 45 and Up Study, with linkage to death records to December 24, 2019. Cumulative absolute risks and population attributable fractions were estimated. Over a median 11.4 years, there were 18,193 deaths. Every additional seven drinks/week increased risk of death from: alcohol-related cancers combined by 12% (HR=1.12; 95%CI=1.05-1.18); digestive system disease by 32% (1.33; 1.22-1.44); falls by 23% (1.23; 1.03-1.46); cardiovascular disease by 7% (1.07; 1.03-1.11); alcohol-related causes combined by 10% (1.10; 1.07-1.12); and from all-cause mortality by 6% (1.06; 1.04-1.08). By age 85 years, men and women who consumed >10 drinks/week were estimated to have 8.5% and 4.1% higher cumulative absolute risk of mortality from alcohol-related causes, respectively, compared to those consuming 0 to <1 drink/week. An estimated 9029 deaths (5.3% of all deaths) were attributable to alcohol consumption in Australia in 2021. Excess risk of death from alcohol consumption in Australia is substantial. Given relatively high alcohol intake, interventions aimed at reducing consumption may translate into significant public health gains.

Pharmacokinetic/pharmacodynamic analysis of tedizolid phosphate against Staphylococcus aureus and Streptococcus pneumoniae in children, adolescents, and adults by Monte Carlo simulation

The objective of this study was to investigate the cumulative fraction of response of various dosage regimens of tedizolid phosphate against Staphylococcus aureus and Streptococcus pneumoniae in children, adolescents, and adults. Monte Carlo simulations (MCSs) were performed using previously published pharmacokinetic parameters and pharmacodynamic data to evaluate the efficacy of the simulated dosage strategies in terms of area under the concentration-time curve/minimum inhibitory concentration targets of tedizolid. According to the results of the MCSs, currently approved dosage regimens of tedizolid phosphate were effective in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) including vancomycin intermediate, heterogeneous vancomycin intermediate, and daptomycin-non-susceptible MRSA in adult and pediatric patients aged 12 years and older. However, high-dose regimens of tedizolid phosphate should be the preferred option to optimize efficacy against ABSSSIs caused by linezolid-resistant MRSA, particularly cfr-mediated isolates. Furthermore, the dosage regimens of 3 and 4 mg/kg/day of tedizolid phosphate were appropriate to treat ABSSSIs caused by MSSA and MRSA in children aged 2 to 6 and 6 to 12 years, respectively. Moreover, approved dosage regimens of tedizolid phosphate for patients older than 12 years may be sufficient against Streptococcus pneumoniae pneumonia but insufficient for Staphylococcus aureus pneumonia. For neutropenic patients, almost all the simulated regimens of tedizolid phosphate were ineffective against Staphylococcus aureus and Streptococcus pneumoniae. These pharmacokinetics/pharmacodynamics-based simulations rationalize and optimize the dosage regimens of tedizolid phosphate against Staphylococcus aureus and Streptococcus pneumoniae in children, adolescents, and adults.

Fractionation Studies to Increase the Ni Grade of Saprolite Ores from the Wolo Mine Area, Kolaka Regency of Southeast Sulawesi, Indonesia

The raw materials of stainless steel production are mainly derived from nickel laterite ore. The production of stainless steel is carried out using the pyrometallurgical method. The Rotary Kiln Electric Furnace (RKEF) process is widely used to produce ferronickel or nickel matte. The feed for the RKEF smelter originates from saprolite ores and is usually divided into soft saprolite and rocky saprolite. Soft saprolite generally has a higher Ni-grade than rocky saprolite. The potential for increased nickel grade in rocky saprolite can be carried out by screening the bulk ores to minimize gangue materials. In this study, a total of 22 samples of saprolite ore were taken from five different mining fronts and then screened to produce a series of fractions with the size of -2", +2"-4", +4"-6", +6"-8", + 8”. Results of chemical analysis using the XRF method show that enrichment of Ni was found in the -2” fractions, and Ni grade tends to decrease with the larger fraction sizes. Lizardite is the principal nickel-hosted mineral in saprolite ores with the highest composition in the cumulative fraction -2”. Gangue minerals, mainly olivine, significantly affect the enrichment of Ni, especially in the coarser fraction. The higher olivine composition indicates a lower Ni content. The (+6-8)" and (+8)" fractions should be removed to obtain the optimum Ni grade and recovery.

Dose optimization of piperacillin/tazobactam, cefepime, and ceftazidime for carbapenem-resistant Pseudomonas aeruginosa isolates in Türkiye.

Although CRPA may test susceptible to other β-lactams such as ceftazidime (CAZ), cefepime (FEP), and piperacillin/tazobactam (TZP), reduced potency has been observed. We assessed the adequacy of EUCAST Susceptible (S) or Susceptible Increased Exposure (SIE)/(I) doses for CAZ, FEP, and TZP against CRPA clinical isolates. CRPA isolates were collected from patients at three Turkish hospitals. CAZ, FEP, and TZP MICs were determined using broth microdilution. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) for a free time above the MIC (fT > MIC) targets for various doses of each agent against isolates defined as susceptible. fT > MIC targets were 70% for CAZ or FEP and 50% for TZP. Cumulative fraction of response (CFR) was calculated. Optimal PTA and CFR was 90% target achievement. The percentages of isolates SIE/I to CAZ, FEP, and TZP were 49,8%, 47%, and 31,8% respectively. Reduced potency was noted with 54,1% of CAZ-S isolates having MICs of 4 or 8mg/L. Of the FEP and TZP-S isolates, MICs at the breakpoint (8 and 16mg/L, respectively) were the mode with 45,2 and 53,9% of isolates for each, respectively. At an MIC of 8mg/L for CAZ, the EUCAST standard dose was insufficient (CFR of 85%). 3h infusions of EUCAST SIE doses were required for 90% PTA at MIC of 8mg/L and an optimized CFR of 100%. For FEP, the SIE dose of 2g q8h 0.5h infusion of was effective (CFR 96%), utilization of an extended 3h infusion further optimized the PTA at 8mg/L (CFR 99%). For TZP, the standard dose of 4.5 q6h administered as a 0.5h infusion was inadequate (CFR 86%). A standard TZP dose with an extended infusion (4.5g q8h over 4h) and the SIE dose 4.5g q6h 3h infusion resulted in CFRs > 95%. These data support the EUCAST SIE breakpoints for FEP and TZP. To optimize PTA at the SIE breakpoint for CAZ, prolonged infusion is required.

Theoretical Model and Experimental Application for Solute Diffusion in Leaching Test With Time-Dependent Boundary Conditions

Abstract Measuring the diffusion coefficient of clay-based liner materials is important in estimating and predicting long-term barrier performance in waste containment facilities. Various theoretical models, including the finite cylindrical model, have been commonly used to determine the diffusion properties of clay-based liner materials in leaching tests. However, the assumption of zero-concentration boundary conditions of the traditional finite cylindrical model contradicts the measured variation of concentration in real leaching tests, likely resulting in (1) underestimated and unconservative diffusion coefficient, or (2) requirement of a relatively large liquid-to-soil ratio and frequent leachate replacement in the experiment to maintain the zero-concentration boundary condition. In this study, a theoretical model was developed to evaluate the solute diffusion process within a soil specimen under arbitrary, time-dependent concentration boundary conditions. The proposed model, incorporating the time-dependent boundary conditions, provides efficient calculations of the concentration distribution and the cumulative fraction leached of solute across the soil specimen. The example application of the proposed model to experimental data demonstrates the capability of the proposed model to determine apparent diffusion coefficients of clay-based liner materials without introducing errors associated with the assumption of a zero concentration boundary condition. The proposed model provides a comprehensive method to investigate the dynamic transport behaviors of solutes through clay-based liner materials in future studies.

Monte Carlo simulation for dosage optimization of the best available therapy for bloodstream infections secondary to carbapenemase-producing Klebsiella pneumoniae in critically ill patients

ObjectiveWe aimed to use Monte Carlo simulation, based on pharmacokinetic/pharmacodynamic targets, to investigate and determine the optimal dosage of the available combination therapies for carbapenem-resistant Klebsiella pneumoniae (CRKP) in critically ill patients. MethodsWe collected CRKP clinical isolates from Phramongkutklao Hospital between October 2020 and June 2022. A molecular study of resistant genes was performed using polymerase chain reaction. Broth microdilution checkerboards were used to evaluate the mono- and synergistic antibiotic activities. Monte Carlo simulation was used to determine the optimal antibiotic regimens, based on the probability of target attainment (PTA) and cumulative fraction of response. ResultsThe 54 CRKP isolates were resistant to tigecycline (100%), colistin (75.9%), amikacin (70.4%), and gentamicin (63.0%). The most common carbapenemase genotype was blaoxacillinases (OXA)-48-like (42.6%), followed by blaNew Delhi metallo beta-lactamase (NDM) (29.6%) and coexistence of blaOXA-48-like and blaNDM (22.2%). Based on the PTA, synergistic and additive activities against CRKP isolates were observed with appropriate dosages of tigecycline–colistin (67.9%), tigecycline–gentamicin (62.2%), and tigecycline–amikacin (51.4%). ConclusionsTigecycline–colistin was the best available combination therapy for critically ill patients with CRKP, especially NDM. When used in combination with tigecycline, a colistin creatinine clearance of <90 mL/min can raise the cumulative fraction of response target and less nephrotoxicity.

Evaluating omadacycline dosing regimens against drug-resistant pathogens including Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae in adults: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation.

The objective of this study was to evaluate the efficacy of various dosing regimens of omadacycline against main drug-resistant pathogens in the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). Monte Carlo simulations were conducted using pharmacokinetic parameters and pharmacodynamic data to calculate cumulative fractions of response (CFRs) in terms of drug area under the concentration curve/minimum inhibition concentration targets.CFR ≥ 90% was considered optimal for a dosage regimen. CFR of any approved oral/intravenous regimen with loading-dose was ≥ 90% against methicillin-resistant Staphylococcus aureus (MRSA) for ABSSSI and penicillin-resistant Streptococcus pneumonia, tetracycline-resistant Streptococcus pneumonia, MRSA and β-lactamase positive Haemophilus influenzae for CABP. In conclusion, approved oral/intravenous loading and maintenance doses of omadacycline showed enough efficacy in the treatment of ABSSI and CABP caused by the main drug-resistant pathogens.

Study on Phase Change Materials' Heat Transfer Characteristics of Medium Temperature Solar Energy Collection System.

Within the next five years, renewable energy is expected to account for approximately 80% of the new global power generation capacity, with solar power contributing to more than half of this growth. However, the intermittent nature of solar energy remains a significant challenge to fully realizing its potential. Thus, efficient energy storage is crucial for optimizing the effectiveness and dependability of renewable energy. Phase-change materials (PCMs) can play an important role in solar energy storage due to their low cost and high volumetric energy storage density. The low thermal conductivity of PCMs restricts their use for energy storage, despite their immense potential. Hence, the primary goal of this study is to experimentally investigate the energy storage capacity of two blended phase-change materials (paraffin and barium hydroxide octahydrate) through integration with a medium-temperature solar heat collection system. The experimental findings reveal that the blended PCMs possess the highest cumulative charge fraction (0.59), energy capacity, and low energy loss compared to each PCM alone. Furthermore, the phase change storage tank achieves higher heat storage (27%) and exergy storage efficiency (18%) compared to the stored tank water without any PCMs. The blended PCMs enhanced their performance, exhibiting improved interaction and excellent thermal storage properties across a range of temperatures, offering an opportunity for the design of an energy-efficient, low-cost storage system.

Impact of mountain-wave-induced temperature fluctuations on the occurrence of polar stratospheric ice clouds: a statistical analysis based on MIPAS observations and ERA5 data

Abstract. Temperature fluctuations induced by mountain waves can play a crucial role in the formation of polar stratospheric clouds (PSCs). In particular, the cold phase of the waves can lower local temperatures sufficiently to trigger PSC formation, even when large-scale background temperatures are too high. To provide new quantitative constraints on the relevance of this effect, this study analyzes a decade (2002–2012) of ice PSC detections obtained from Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) measurements and ERA5 data in the polar winter lower stratosphere. In the MIPAS observations, we find that approximately 52 % of the Arctic ice PSCs and 26 % of the Antarctic ice PSCs are detected at temperatures above the local Tice. Ice PSCs above Tice are concentrated around mountainous regions and their downwind directions. A backward-trajectory analysis is performed to investigate the temperature history of each ice PSC observation. The cumulative fraction of ice PSCs above Tice increases as the trajectory gets closer to the observation point. The most significant change in the fraction of ice PSCs above Tice occurs within the 6 h preceding the observations. At the observation point, the mean fractions of ice PSCs above Tice, taking into account temperature fluctuations along the backward trajectory, are 33 % in the Arctic and 9 % in the Antarctic. The results provide a quantitative assessment of the occurrence of ice PSCs above Tice in connection with orographic waves. Additionally, the observational statistics presented can be utilized for comparison with chemistry climate simulations.

Optimized fosfomycin regimens for treating carbapenem-resistant Acinetobacter baumannii in criticallyill patients with varying degrees of renal function.

Fosfomycin has been used to treat carbapenem-resistant Acinetobacter baumannii (CRAB) infections. However, there is insufficient information on dosage adjustment among critically ill patients with renal impairment. This study aims to evaluate the attainment of PK/PD targets for different dosage regimens of CRAB treatment in critically ill patients based on their renal function. Monte Carlo simulations were conducted to assess the probability of achieving time above the minimum inhibitory concentration (T > MIC) of 80% and 100% and to determine the cumulative fraction response (CFR) against institutional MICs. Our results demonstrated that administering fosfomycin 20-24 g/day to individuals with normal renal function (CrCl ≥60 mL/min) achieved the target at a MIC of ≤64 and ≤32 μg/mL during the first 24 h of treatment and at steady state, respectively. Notably, those with renal impairment achieved higher MIC values at a steady state despite dosage reduction. None of the regimens reached the target CFR. Our study suggested that administering fosfomycin at least 20 g/day to those with normal renal function provides sufficient exposure throughout the treatment course when the MIC value is ≤32 μg/mL. Less aggressive dosing regimens are advisable for patients with renal impairment. Additional clinical studies are necessary to verify our suggestions.

Corrosion shielding effect of polyaluminium sulphate on metallic aluminium during the solidification of radioactive incineration bottom ash by low alkalinity cement

Radioactive incineration bottom ash containing metallic Al is difficult to be directly solidified in the cement matrix due to the generation of hydrogen gas during the reaction of aluminium with alkali pore solution of cement paste. In this study, the simulated incineration bottom ash (SIBA) containing metallic Al was successfully and directly solidified by polyaluminium sulphate (PAS)-modified low alkalinity cement (LAC), and the mechanism of the corrosion shielding effect of PAS on metallic Al was characterized by a range of analytical techniques. The results indicate that the cement waste form containing 29.56 wt% SIBA achieved a compressive strength of 16.6 MPa at 28 days of hydration, which increased by 13.3 % and 36.1 % after freeze-thawing test and immersion test, respectively. The 42d cumulative fraction leached of Nd3+ and Ce3+ were 1.74×10−7 cm and 3.40×10−7 cm, respectively. The corrosion degree and corrosion rate of Al sheets in LAC with PAS addition was much lower than that without PAS at early and late age hydration, by transforming thick porous corrosion layer to thin dense one. The mineral phase of corrosion product remained as bayerite (Al(OH)3), regardless of whether PAS was added. The addition of PAS reduced the hydrogen gas generation and prevented the dissolution of Al(OH)4- from metallic Al sheet. The hydrolysis of PAS produced a large amount of Al(OH)4- in pore solution, which extended the pH range for Al(OH)3 passivation by preventing the transformation of Al(OH)3 protection layer on the Al sheet surface to Al(OH)4- in the pore solution, and accelerated the formation of ettringite to decrease the pH of pore solution. This study cast the light on the direct solidification of metallic-aluminium-containing incineration bottom ash or Al bulks by cement-based materials without the need for complex pretreatment processes.

Optimization of high-temperature thermal pretreatment conditions for maximum enrichment of lithium and cobalt from spent lithium-ion polymer batteries

Due to their increasingly high demand, lithium-ion batteries (LIBs) will encounter a scarcity of essential resources if recycling is not prioritized. The current pretreatment methods for spent LIBs used in industrial production are inefficient, costly, and hazardous. The study aimed to maximize the yield of lithium and cobalt from the black mass of spent Lithium-ion batteries through an optimized high-temperature thermal pretreatment process, which combined mechanical (direct crushing) and thermal treatments to facilitate the subsequent recovery of these valuable metals. Sieve analysis showed that direct crushing for 2 min resulted in 40.81 % of the anode material in the 4750 + 2500 μm size range, while 5 min of crushing led to a more even distribution, with 28.57 % in the smallest size range (−75 μm). Heat treatment followed by 2 min of crushing concentrated 52.38 % of the anode material in the 4750 + 2500 μm range. For the cathode material, 2 min of direct crushing distributed 24.49 % in the −2500 + 1250 μm range, while 5 min of crushing accumulated 38.80 % in the −75 μm range. Heat treatment and 2 min of crushing resulted in 56.05 % of the cathode material in the −75 μm range, indicating improved liberation. The combination of heat treatment and mechanical treatment effectively liberates and reduces the size of the active materials, resulting in a higher cumulative mass fraction of finer particles (≤630 μm). Heat treatment at 600 °C for 15 min, followed by 2 min of crushing, dissociated current collectors (Al) from the cathode material, minimized the harmful gas emissions and produced fine particles (630 μm) with minimal Al content (0.8 wt%). The optimal heat treatment condition of 600 °C for 35 min achieved complete decomposition of PVDF and enriched 73.49 wt% cobalt and 5.41 wt% lithium in the black mass, superior to previous studies.

Vascular refilling in hemodialysis using feedback-controlled ultrafiltration profile.

The rate and the duration of ultrafiltration (UF) are considered the most important factors to affect vascular refilling. The aim of the study was to investigate whether a UF profile could improve the vascular refilling. Dialysis was delivered by a machine providing feedback control of ultrafiltration rates. Absolute blood volume (BV) was measured by dialysate bolus method. Vascular refilling volume (Vref) was calculated as UF volume - Δ absolute BV. In 40 patients, refilling fraction (Vref/UF volume) was 30.5% in the first hour. Thereafter, refilling fraction steeply increased and reached maximum values in the third and fourth hour at about 95%. The cumulative refilling fraction was 68.5 ± 9.4% at the end. In 14 patients, refilling data from the feedback-controlled UF profile were compared to dialysis sessions with constant UF rates. In 12 of 14 patients, refilling fraction was significantly (p = 0.013) higher in sessions with UF profile (71.6% vs 64.4%).There was a significant negative correlation (r = -0.606; p = 0.002) between the blood volume to extracellular volume ratio and the refilling fraction. The sum of this ratio and the refilling fraction was 1.01 ± 0.06. Despite significant differences, a feedback-controlled UF profile has no advantage over the previous refilling studies with regard to the refilling fraction because vascular refilling seems to depend mainly on the ratio of BV to ECV. This would explain the different results in studies using BV guided UF feedback programs.

Optimization of oral isavuconazole dose for population in special physiological or pathological state: a physiologically based pharmacokinetics model-informed precision dosing.

To recommend precision dosing and improve therapeutic efficacy against invasive fungal disease, a physiologically based pharmacokinetic model (PBPK) of oral isavuconazole (ISA) was established and used to explore its disposition across populations in different physiological and pathological states. Twenty-five pharmacokinetic (PK) studies of oral ISA were identified through a systematic search of PubMed. Concentration-time data were extracted using WebPlotDigitizer. Physiochemical parameters were obtained from published literature and DrugBank. Model development and simulation used the Simcyp population-based simulator, and visual predictive check and predictive error were used for the model evaluation. Probability of target attainment and the cumulative fraction of response analyses were performed for dose optimization. The developed PBPK model was successfully validated in different populations. Most predicted concentration-time points aligned with the observed data, with acceptable predictive errors for the critical parameters. We predicted the PK profiles and parameters of ISA in a population with severe hepatic impairment (HI), a population with obesity and paediatric patients aged 1 to less than 6 years old. The probability of target attainment and cumulative fraction of response analyses indicated that the population with severe HI should have half the maintenance dose. The population with obesity and population with severe HI should have a loading dose of 300 mg every 8 h for 2 days. For paediatric patients aged 1 to less than 6 years old, a weight-based dosing regimen (5.38 mg/kg) of ISA was suggested. The predicted value aligns with observations, suggesting ISA's potential predictability in PK profiles for other populations. The recommended dosing regimens increase our understanding of the use of ISA in special populations.

Distribution and characterization of products obtained from pyrolysis of cooked food waste- Impact of heating rate

This work offers a comprehensive investigation of the pyrolysis products—liquid, gas, and solid derived from cooked food waste (CFW) at different heating rates (15–100 °C/min). The heating rate significantly influenced the yield of pyrolysis products. The maximum yield of bio-oil (oil + aqueous) was achieved at a heating rate of 50 °C/min, py-gas at 100 °C/min, and biochar at 15 °C/min. The yields were 34 wt% for bio-oil, 30 wt% for py-gas, and 32 wt% for biochar. Analysis of the bio-oil revealed significant proportions of fatty acids (Methyl-methyltetradecanoate) and esters (Oleic acid ethyl ester), constituting 25 %, and 26 % at 15 °C/min but declining with increasing heating rates. Another ester (9-Octadecenoic acid methyl ester) was found across all heating rate with highest concentration of 33 % at 100 °C/min. Aliphatic hydrocarbons (Octane, Dodecene, Heptadecane, Tetradecyne, Undecane, Dimethylhepta-1,3-triene, Tetradecane, Nonadecane), constituted highest concentration of 12 % at 25 °C/min and aromatic hydrocarbons (Toluene) showed maximum presence of 4 % at 50 °C/min. The aqueous phase showcased cyclic nitrogenated compounds (Piperidine), anhydrosugars (DGP), and furanics (Furanmethanol), with the highest concentrations of 46 %, 12 %, and 38 %, respectively observed at 100 °C/min. Instantaneous py-gas analysis indicated an elevated presence of CO2 and CO in the initial pyrolysis stages (up to 70 min) followed by higher H2 in the latter stages (>70 min). While increasing heating rates (15–100 °C/min) boosted cumulative fractions of CO2 and CO, the highest H2 fraction was observed at 50 °C/min. The proximate and ultimate analysis of biochars indicated increased ash, fixed carbon, HHV and H/C compared to raw CFW. The surface area and morphology were positively influenced by an increase in heating rate, resulting in a microporous biochar having maximum surface area of 340.6 m2/g at 50 °C/min.

Adequacy of the Dosing and Infusion Time of Ceftazidime/Avibactam for the Treatment of Gram-Negative Bacterial Infections: A PK/PD Simulation Study.

Recent studies suggested the potential benefits of extended infusion times to optimize the treatment efficacy of ceftazidime/avibactam, which indicated that the current pharmacokinetic/pharmacodynamic (PK/PD) target may not be sufficient, especially for severe infections. The purpose of this study is to assess the adequacy of dosing strategies and infusion durations of ceftazidime/avibactam when applying higher PK/PD targets. This study utilized published PK parameters to conduct Monte Carlo simulations. Different dosages including the recommended regimen based on renal function were simulated and evaluated by the probability of target attainment (PTA) and cumulative fraction of response (CFR). Different PK/PD targets were set for ceftazidime and avibactam. MIC distributions from various sources were used to calculate the CFR. Multiple PK/PD targets have been set in this study, All recommended dosage could easily achieve the target of 50%fT ≥ MIC (ceftazidime) and 50%fT ≥ CT=1.0 mg/L (avibactam). However, for severe infection patients with normal renal function and augmented renal clearance at the recommended dosage (2000 mg/500 mg, every 8 hours), the infusion duration needs to be extended to 3 hours and 4 hours to achieve the targets of 100%fT ≥ MIC and 100%fT ≥ CT=1.0 mg/L. Only continuous infusion at higher dosages achieved 100%fT ≥ 4×MIC and 100%fT ≥ CT=4.0 mg/L targets to all currently recommended regimens. According to the varying MIC distributions, higher concentrations are needed for Pseudomonas aeruginosa, with the attainment rates vary across different regions. The current recommended dosing regimen of ceftazidime/avibactam is insufficient for severe infection patients, and continuous infusion is suggested.

Bidimensional Exploration of the warm-Temperature Ionised gaS (BETIS)

We present the Bidimensional Exploration of the warm-Temperature Ionised gaS (BETIS) project, designed for the spatial and spectral study of the diffuse ionised gas (DIG) in a selection of nearby spiral galaxies observed with the MUSE integral-field spectrograph. Our primary objective is to investigate the various ionisation mechanisms at play within the DIG. We analysed the distribution of high- and low-ionisation species in the optical spectra of the sample on a spatially resolved basis. We introduced a new methodology for spectroscopically defining the DIG, optimised for galaxies of different resolutions. Firstly, we employed an innovative adaptive binning technique on the observed datacube based on the spectroscopic signal-to-noise ratio (S/N) of the collisional [S II] line to increase the S/N of the rest of the lines including [O III], [O I], and He I. Subsequently, we created a DIG mask by eliminating the emissions associated with both bright and faint H IIregions. We also examined the suitability of using Hαequivalent width (EWHα) as a proxy for defining the DIG and its associated ionisation regime. Notably, for EWHα &lt; 3 Å – the expected emission from hot low-mass evolved stars (HOLMES) – the measured value is contingent on the chosen population synthesis technique performed. Our analysis of the showcase sample reveals a consistent cumulative DIG fraction across all galaxies in the sample, averaging around 40%–70%. The average radial distribution of the [N II]/Hα, [S II]/Hα, [O I]/Hα, and [O III]/Hβratios are enhanced in the DIG regimes (up to 0.2 dex). It follows similar trends between the DIG regime and the H IIregions, as well as the Hαsurface brightness (ΣHα), indicating a correlation between the ionisation of these species in both the DIG and the H IIregions. The DIG loci in typical diagnostic diagrams are found, in general, within the line ratios that correspond to photoionisation due to the star formation. There is a noticeable offset correspondent to ionisation due to fast shocks. However, an individual diagnosis performed for each galaxy reveals that all the DIG in these galaxies can be attributed to photoionisation from star formation. The offset is primarily due to the contribution of Seyfert galaxies in our sample, which is closely aligned with models of ionisation from fast shocks and galactic outflows, thus mimicking the DIG emission. Our results indicate that galaxies exhibiting active galactic nucleus (AGN) activity should be considered separately when conducting a general analysis of the DIG ionisation mechanisms, since this emission is indistinguishable from high-excitation DIG.

Optimizing Antibiotic Therapy for Stenotrophomonas maltophilia Infections in Critically Ill Patients: A Pharmacokinetic/Pharmacodynamic Approach.

Stenotrophomonas maltophilia is an opportunistic, multidrug-resistant non-fermentative Gram-negative bacillus, posing a significant challenge in clinical treatment due to its numerous intrinsic and acquired resistance mechanisms. This study aimed to evaluate the adequacy of antibiotics used for the treatment of S. maltophilia infections in critically ill patients using a pharmacokinetic/pharmacodynamic (PK/PD) approach. The antibiotics studied included cotrimoxazole, levofloxacin, minocycline, tigecycline, cefiderocol, and the new combination aztreonam/avibactam, which is not yet approved. By Monte Carlo simulations, the probability of target attainment (PTA), the PK/PD breakpoints, and the cumulative fraction of response (CFR) were estimated. PK parameters and MIC distributions were sourced from the literature, the European Committee on Antimicrobial Susceptibility Testing (EUCAST), and the SENTRY Antimicrobial Surveillance Program collection. Cefiderocol 2 g q8h, minocycline 200 mg q12h, tigecycline 100 mg q12h, and aztreonam/avibactam 1500/500 mg q6h were the best options to treat empirically infections due to S. maltophilia. Cotrimoxazole provided a higher probability of treatment success for the U.S. isolates than for European isolates. For all antibiotics, discrepancies between the PK/PD breakpoints and the clinical breakpoints defined by EUCAST (or the ECOFF) and CLSI were detected.

A new fatigue equation for asphalt mixtures considering loading sequence effects

The fatigue life of asphalt mixture has been found to significantly depend on loading sequences. However, the widely used traditional linear fatigue equations are difficult to determine the fatigue life of asphalt mixture subjected to different loading sequences. This study aims to improve these fatigue equations by establishing a fatigue equation considering loading sequence effects. First, the semi-circular bending (SCB) constant amplitude fatigue tests were conducted under the high loading amplitude (σhigh) and low (σlow) loading amplitude, respectively. Then, two of the loading sequences, namely the low-high stress (σlow-σhigh) and high-low stress (σhigh-σlow), were selected to carry out the SCB variable amplitude fatigue tests. Furthermore, the loading sequence effects on the life fractions and fatigue life of asphalt mixtures were analyzed. Finally, the damage equivalent criterion was successfully applied to establish the nonlinear fatigue damage accumulation model and fatigue equation considering loading sequence effects. It was found that the cumulative life fractions of asphalt mixtures under constant amplitude loading are equal to 1, indicating the linear fatigue damage accumulation. The cumulative life fractions corresponding to the σlow-σhigh and σhigh-σlow are greater than 1 and less than 1, respectively, indicating the nonlinear fatigue damage accumulation. The established nonlinear fatigue damage accumulation model can accurately characterize the dependence of fatigue damage accumulation on loading sequences. The established fatigue equations can improve the traditional linear fatigue equations to some extent and accurately predict the fatigue life of asphalt mixtures corresponding to the loading sequences of the σlow-σhigh and σhigh-σlow.

Transfer of the Dual Orexin Receptor Antagonist Daridorexant into Breast Milk of Healthy Lactating Women.

The novel dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of adult patients with insomnia. The aim of this post-marketing study was to measure daridorexant and its major metabolites in breast milk and plasma of 10 healthy lactating subjects. This single-center, open-label study evaluated the transfer of the analytes into breast milk. A single dose of 50 mg was orally administered in the morning. Milk and blood samples were collected pre-dose and over a period of 72 h after dosing. The pharmacokinetics of daridorexant in milk and plasma were assessed including the cumulative amount and fraction of dose excreted, daily infant dose, and relative infant dose. Safety and tolerability were also investigated. All subjects completed the study. Daridorexant was rapidly absorbed into and distributed from plasma. Daridorexant and its major metabolites were measurable in breast milk. The cumulative total amount of daridorexant excreted over 72 h was 0.010 mg, which corresponds to 0.02% of the maternal dose. This corresponds to a mean daily infant dose of 0.009 mg/day and a relative infant dose of less than 0.22% over 24 h. The maternal safety profile was similar to that observed in previous studies. Low amounts of daridorexant and its metabolites were detected in the breast milk of healthy lactating women. Since the exposure and potential effects on the breastfed infant are unknown, a risk of somnolence or other depressant effects cannot be excluded.