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The possibility of attaining direct compression (DC) tableting using silica coated fine particle sized excipients was examined for high drug loaded (DL) binary blends of APIs. Three APIs, very-cohesive micronized acetaminophen (mAPAP, 7 μm), cohesive acetaminophen (cAPAP, 23 μm), and easy-flowing ibuprofen (IBU, 53 μm), were selected. High DL (60 wt%) binary blends were prepared with different fine-milled MCC-based excipients (ranging 20- 37 μm) with or without A200 silica coating during milling. The blend flowability (flow function coefficient -FFC) and bulk density (BD) of the blends for all three APIs were significantly improved by 1 wt% A200 dry coated MCCs; reaching FFC of 4.28 from 2.14, 7.82 from 2.96, and > 10 from 5.57, for mAPAP, cAPAP, and IBU blends, respectively, compared to the uncoated MCC blends. No negative impact was observed on the tablet tensile strength (TS) by using dry coated MCCs despite lower surface energy of silica. Instead, the desired tablet TS levels were reached or exceeded, even above that for the blends with uncoated milled MCCs. The novelty here is that milled and silica coated fine MCCs could promote DC tableting for cAPAP and IBU blends at 60 wt% DL through adequate flowability and tensile strength, without having to dry coat the APIs. The effect of the silica amount was investigated, indicating lesser had a positive impact on TS, whereas the higher amount had a positive impact on flowability. Thus, the finer excipient size and silica amounts may be adjusted to potentially attain blend DC processability for high DL blends of fine APIs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We investigate the environmental properties of the z  = 0 radio galaxy population using the simba cosmological hydrodynamic simulation. We identify centrals and satellites from a population of high and low excitation radio galaxies (HERGs and LERGs) in simba, and study their global properties. We find that [Formula: see text] of radio galaxies are satellites, and that there are insignificant differences in the global properties of LERGs based on their central/satellite classification. HERG satellites display lower values of star formation, 1.4 GHz radio luminosity, and Eddington fractions than HERG centrals. We further investigate the environments of radio galaxies and show that HERGs typically live in less dense environments, similar to star-forming galaxies. The environments of high-mass LERGs are similar to non-radio galaxies, but low-mass LERGs live in underdense environments similar to HERGs. LERGs with overmassive black holes reside in the most dense environments, while HERGs with overmassive black holes reside in underdense environments. The richness of a LERG's environment decreases with increasing Eddington fraction, and the environments of all radio galaxies do not depend on radio luminosity for [Formula: see text]. Complementing these results, we find that LERGs cluster on the same scale as the total galaxy population, while multiple HERGs are not found within the same dark matter halo. Finally, we show that high density environments support the growth of HERGs rather than LERGs at z  = 2. Simba predicts that with more sensitive surveys, we will find populations of radio galaxies in environments much similar to the total galaxy population., (© 2022 The Author(s) Published by Oxford University Press on behalf of Royal Astronomical Society.)

Chronic granulomatous disease (CGD) is an inborn error of immunity caused by inactivating genetic mutations in any one of the components of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Phagocytic cell reactive oxygen species generation is impaired in the absence of a functional NADPH oxidase complex. As a result, patients with CGD are at high risk of developing deep-seated infections with certain bacteria and fungi. Additionally, aberrant inflammation and granuloma formation may occur in multiple organs including the bowels, with inflammatory bowel disease seen as a common inflammatory complication of CGD. Traditionally, TNF-α inhibitors are considered effective biological therapies for moderate-to-severe inflammatory bowel disease. While limited case series and reports of patients with CGD have shown improvement in fistula healing with use of TNF-α inhibitors, several patients have developed severe, even fatal, infections with CGD-related pathogens while on TNF-inhibitor therapy. In this case report, we describe an adolescent male with X-linked CGD and steroid-refractory colitis with perirectal fistula and abscesses, who was initiated on treatment with infliximab, a TNF-α inhibitor. Following his first two infliximab doses, the patient developed a Candida glabrata lymphadenitis and associated ulcerating oropharyngeal lesions, requiring hospitalization and therapy with amphotericin B for resolution. We compare our patient's case to prior reports of infliximab use in CGD-related inflammatory bowel disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lehman and Davé.)

We identified deep diabetic foot infections by culture and conducted a case-control study examining the risk factors for moderate to severe methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PsA) diabetic foot infections. Our MRSA prevalence was lower than literature values; PsA was higher. Gangrene may be predictive of Pseudomonas infection., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Urine cultures are often positive in the absence of a urinary tract infection (UTI). Pyuria is generally considered necessary to diagnose a UTI., Problem: Urine cultures are often positive in the absence of UTI leading to unnecessary antibiotics., Methods: Quasi-experimental pre-post study of all patient urine cultures ordered in a VA acute care hospital, emergency department (ED), and two long-term care (LTC) facilities from August 2016 to August 2018. Urine cultures performed per 100 days were compared pre- (August 2016 to July 2017) versus post-intervention (August 2017 to August 2018) using interrupted time series negative binomial regression., Intervention: We examined whether reflexing to urine culture only if a urinalysis (UA) found greater than 10 WBC/hpf decreased urine culturing., Results: In acute-care, reflex culturing resulted in a 39% time series regression analysis adjusted decrease in the rate of cultures performed (pre-intervention, 3.6 cultures/100 days vs. Post-intervention, 1.8 cultures/100 days, p < 0.001). Pre-intervention, 29% (4/14) of Catheter-associated UTI (CAUTI) would not have been reported if reflex culturing was employed. In the ED, reflex culturing was associated with a 38% (p = 0.0015) regression analysis adjusted decrease in cultures, from 5.4/100 visits to 3.3/100 visits. In LTC, there was a small absolute, but regression analysis adjusted increase of 89% (p = 0.0018) in rates from (0.4/100 days to 0.5/100 days)., Conclusion: In acute care and ED, urine reflex culturing decreased the number of urine cultures performed. A small absolute increase was seen between pre-post time periods in LTC. Reflex testing generally decreases cultures and may lead to more accurate diagnoses of CAUTI.

Left main bifurcation percutaneous coronary intervention is a challenging subset that requires expertise in techniques that are in constant modification. Imaging is important in lesion preparation and optimising outcomes. The interventionalist needs to be highly skilled in the different techniques, as missteps may lead to stent thrombosis and critical in-stent restenosis. Lesion classification between simple and complex identifies those who would best benefit from a two-stent technique. Current technical approaches and practice considerations are summarised in this manuscript., Competing Interests: Disclosures: J Dawn Abbott has received research grants (institutional, no financial compensation) from Abbott Vascular Inc., Astra Zeneca, Sinomed, CSL Behring and Biosensors Research, and is a consultant for Philips. Mir Babar Basir is a consultant for Abbott Vascular, Abiomed, Cardiovascular Systems, Chiesi and Zoll. Azeem Latib is a consultant, and is on the Advisory Board, for Medtronic, Abbott, Boston Scientific and Philips. Perwaiz Meraj is a consultant for Abiomed. Kevin Croce has received grant/research support from Abbott, Takeda, Teleflex and CSI, and has received consulting fees/honoraria from Abbott, BSCI, Biotronik, Philips, Abiomed, CSI, Takeda and Cordis, and is a major stock shareholder/equity for Dyad Medical. Rajesh Davé is a speaker for Abbot Vascular and is a speaker for, and receives fees from, Proctor. Tanveer Rab and Gautam Kumar have nothing to disclose in relation to this article., (© Touch Medical Media 2020.)

Introduction: Dalbavancin is approved for acute bacterial skin and skin structure infections (ABSSSIs) but offers a potential treatment option for complicated invasive gram-positive infections. Importantly, dalbavancin's real benefits may be in treating complicated infections in vulnerable patient populations, such as persons who inject drugs (PWID)., Methods: A multicenter retrospective analysis was performed from March 2014 to April 2017 to assess 30- and 90-day clinical cure and adverse drug events (ADEs) in adult patients who received ≥ 1 dose of dalbavancin for a non-ABSSSI indication., Results: During the study period, 45 patients received dalbavancin, 28 for a non-ABSSSI indication. The predominant infections treated included osteomyelitis (46%), endovascular infection (25%) and uncomplicated bacteremia (14%). Half of the patients had positive Staphylococcus aureus in cultures, 29% methicillin resistant and 21% methicillin susceptible. Most patients were prescribed dalbavancin as sequential treatment with a median of 13.5 days of prior antibiotic therapy. The most common reason for choosing dalbavancin over standard therapy use was PWID (54%). Seven patients were lost to follow-up at day 30. Of the remaining evaluable patients, 30-day clinical cure was achieved in 15/21 (71%) patients. The most common reason for failure was lack of source control (4/6, 67%). At day 90, relapse occurred in two patients. Three patients had a potential dalbavancin-associated ADE: two patients with renal dysfunction and one patient with pruritus., Conclusions: This study demonstrates a possible role for dalbavancin in the treatment of non-ABSSSI invasive gram-positive infections in select vulnerable OPAT patients.

It has been shown that dry coating cohesive active pharmaceutical ingredients (APIs) with nano-silica can improve packing and flow of their blends, facilitating high speed direct compression tableting. This paper examines the broader scope and generality of previous work by examining three fine APIs; micronized Acetaminophen (mAPAP), coarse Acetaminophen (cAPAP) and micronized Ibuprofen (mIBU), and considers dry coating with both hydrophobic or hydrophilic nano-silica to examine the effect not only on packing density and flow of their blends, but also dissolution and tensile strength of their tablets. The impact of the excipient size on blend and tablet properties are also investigated, indicating blend flow is most improved when matching API particle size with excipient particle size. In all cases where the API is dry coated, the blend packing and flow improve, so as to suggest such high drug loaded blends could enable direct compression. Using dry coated API along with finer excipients in blends lead to improved hardness of the corresponding tablets. Interestingly, dissolution profiles show dry coated API tablets generally have faster dissolution rates, regardless of silica hydrophilicity, suggesting API powder deagglomeration via nano-silica coating plays a crucial role. The most significant conclusion is that, although there are differences in properties of blends that depend on the API, hydrophobic or hydrophilic nano-silica coating, as well as large or fine excipients, in all cases, dry coating of APIs significantly improves the possibility of using the specific blend at high drug loading in direct compression tableting., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A promising approach to increase the aqueous solubility, hence the bioavailability, of poorly water-soluble drugs is to convert them into their amorphous state through impregnation into mesoporous silica. Unfortunately, mesoporous silica is not yet available in bulk quantities due to high manufacturing costs. In this work, feasibility of using a commercially available cost-effective mesoporous fine grade Neusilin ® UFL2 to prepare amorphous drug composites of 2 model poorly soluble drugs, fenofibrate and itraconazole, is established. In contrast to fluidized-bed spray-impregnation, only mixing and drying steps are required. Complimentary assessment using X-ray powder diffraction, differential scanning calorimetry, and Raman spectroscopy confirmed drug within the composites to be amorphous at as high as 30% drug loading both after formation and after 3 months of storage at 40°C and 75% relative humidity. Amorphous drug recrystallization was completely suppressed due to the confinement effect due to the Neusilin ® . The amorphous drug composites resulted in higher apparent solubility and faster dissolution rate of the model drugs as compared to their crystalline counterpart, confirmed by United States Pharmacopeia II dissolution and ultraviolet surface dissolution imaging. Overall, stable, high drug-loaded fast-dissolving amorphous drug composites preparation using Neusilin ® UFL2 is demonstrated as a promising approach to enhance solubility of poorly soluble drugs., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

In a recent study, it was demonstrated that improving flow of a model poorly flowing and poorly compactable drug substance, acetaminophen, via dry coating while using fine excipients, may promote direct compression. To validate this novel strategy, particularly for high drug-loading formulations, this study investigates the effect of microcrystalline cellulose (MCC) particle size and dry coating on powder tabletability and flowability. It was determined that blends containing fine-sized MCC (20 μm) resulted in the highest tablet tensile strength and best tabletability because it provides higher interparticle contact area compared with coarse-sized MCC. Although tabletability can be improved using fine MCC, flowability is poor but can be improved through dry coating, a process that coats glidants (nano-sized silica) onto particle surfaces. To retain the tabletability, which was adversely affected because of the presence of glidant in the blend, while simultaneously enhancing flowability via dry coating, separately blending the drug substance with glidant is shown to be the best method of processing. The combined use of fine excipients and selective dry coating offers a novel and advantageous formulation strategy in comparison with the conventional use of coarse excipients, such as Avicel PH 102, that have been designed and marketed for direct compression., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Formation of core-shell nanocomposites of Fenofibrate and Itraconazole, model poorly water soluble drugs, via fluidized bed (FB) coating of their well-stabilized high drug loaded nanosuspensions is investigated. Specifically, the extent of dissolution enhancement, when fine carrier particles (sub-50μm) as opposed to the traditional large carrier particles (>300μm) are used, is examined. This allows testing the hypothesis that greatly increased carrier surface area and more importantly, thinner shell for finer carriers at the same drug loading can significantly increase the dissolution rate when spray-coated nanosuspensions are well-stabilized. Fine sub-50μm lactose (GranuLac ® 200) carrier particles were made fluidizable via dry coating with nano-silica, enabling decreased cohesion, fluidization and subsequent nanosuspension coating. For both drugs, 30% drug loaded suspensions were prepared via wet-stirred media milling using hydroxypropyl methyl cellulose and sodium dodecyl sulfate as stabilizers. The stabilizer concentrations were varied to affect the milled particle size and prepare a stable nanosuspension. The suspensions were FB coated onto hydrophilic nano-silica (M-5P) dry coated sub-50μm lactose (GranuLac ® 200) carrier particles or larger carrier particles of median size >300μm (PrismaLac ® 40). The resulting finer composite powders (sub-100μm) based on GranuLac ® 200 were freely flowing, had high bulk density, and had much faster, immediate dissolution of the poorly water-soluble drugs, in particular for Itraconazole. This is attributed to a much higher specific surface area of the carrier and corresponding thinner coating layer for fine carriers as opposed to those for large carrier particles., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: In low/middle income countries like India, diabetes is prevalent and health care access limited. Most adults have a mobile phone, creating potential for mHealth interventions to improve public health. To examine the feasibility and initial evidence of effectiveness of mDiabetes, a text messaging program to improve diabetes risk behaviors, a global nonprofit organization (Arogya World) implemented mDiabetes among one million Indian adults., Objective: A prospective, parallel cohort design was applied to examine whether mDiabetes improved fruit, vegetable, and fat intakes and exercise., Methods: Intervention participants were randomly selected from the one million Nokia subscribers who elected to opt in to mDiabetes. Control group participants were randomly selected from non-Nokia mobile phone subscribers. mDiabetes participants received 56 text messages in their choice of 12 languages over 6 months; control participants received no contact. Messages were designed to motivate improvement in diabetes risk behaviors and increase awareness about the causes and complications of diabetes. Participant health behaviors (exercise and fruit, vegetable, and fat intake) were assessed between 2012 and 2013 via telephone surveys by blinded assessors at baseline and 6 months later. Data were cleaned and analyzed in 2014 and 2015., Results: 982 participants in the intervention group and 943 in the control group consented to take the phone survey at baselne. At the end of the 6-month period, 611 (62.22%) in the intervention and 632 (67.02%) in the control group completed the follow-up telephone survey. Participants receiving texts demonstrated greater improvement in a health behavior composite score over 6 months, compared with those who received no messages F(1, 1238) = 30.181, P<.001, 95% CI, 0.251-0.531. Fewer intervention participants demonstrated health behavior decline compared with controls. Improved fruit, vegetable, and fat consumption (P<.01) but not exercise were observed in those receiving messages, as compared with controls., Conclusions: A text messaging intervention was feasible and showed initial evidence of effectiveness in improving diabetes-related health behaviors, demonstrating the potential to facilitate population-level behavior change in a low/middle income country., Trial Registration: Australian New Zealand Clinical Trials Registry (ACTRN): 12615000423516; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367946&isReview=true (Archived by WebCite at http://www.webcitation.org/6j5ptaJgF).

Preparation of drug nanoparticles via wet media milling (nanomilling) is a very versatile drug delivery platform and is suitable for oral, injectable, inhalable, and buccal applications. Wet media milling followed by various drying processes has become a well-established and proven formulation approach especially for bioavailability enhancement of poorly water-soluble drugs. It has several advantages such as organic solvent-free processing, tunable and relatively high drug loading, and applicability to a multitude of poorly water-soluble drugs. Although the physical stability of the wet-milled suspensions (nanosuspensions) has attracted a lot of attention, fundamental understanding of the process has been lacking until recently. The objective of this review paper is to present fundamental insights from available published literature while summarizing the recent advances and highlighting the gap areas that have not received adequate attention. First, stabilization by conventionally used polymers/surfactants and novel stabilizers is reviewed. Then, a fundamental understanding of the process parameters, with a focus on wet stirred media milling, is revealed based on microhydrodynamic models. This review is expected to bring a holistic formulation-process perspective to the nanomilling process and pave the way for robust process development scale-up. Finally, challenges are indicated with a view to shedding light on future opportunities.

Here we present a sample of 12 massive quiescent galaxy candidates at [Formula: see text] observed with the James Webb Space Telescope (JWST) Near Infrared Spectrograph (NIRSpec). These galaxies were pre-selected from the Hubble Space Telescope imaging and 10 of our sources were unable to be spectroscopically confirmed by ground based spectroscopy. By combining spectroscopic data from NIRSpec with multi-wavelength imaging data from the JWST Near Infrared Camera (NIRCam), we analyse their stellar populations and their formation histories. We find that all of our galaxies classify as quiescent based on the reconstruction of their star formation histories but show a variety of quenching timescales and ages. All our galaxies are massive ([Formula: see text] M[Formula: see text]), with masses comparable to massive galaxies in the local Universe. We find that the oldest galaxy in our sample formed [Formula: see text] M[Formula: see text] of mass within the first few hundred million years of the Universe and has been quenched for more than a billion years by the time of observation at [Formula: see text] ([Formula: see text] billion years after the Big Bang). Our results point to very early formation of massive galaxies requiring a high conversion rate of baryons to stars in the early Universe., (© 2024. Crown.)

Drug nanoparticles in suspensions can form aggregates leading to physical instability, which is traditionally mitigated using soluble polymers and surfactants. The aim of this paper was to explore common superdisintegrants, i.e., sodium starch glycolate (SSG), croscarmellose sodium (CCS), and crospovidone (CP), as novel class of dispersants for enhanced stabilization of fenofibrate (FNB), a model BCS Class II drug, suspensions. FNB was wet-milled with superdisintegrants along with hydroxypropyl methylcellulose (HPMC), a soluble adsorbing polymer, in a stirred media mill. For comparison, FNB was also milled in the presence of HPMC and/or SDS (sodium dodecyl sulfate) without superdisintegrants. Laser diffraction, scanning electron microscopy, viscometry, differential scanning calorimetry, and powder X-ray diffraction were used to characterize the suspensions. The results show that 2% HPMC along with 1% SSG or 1% CCS mitigated the aggregation of FNB nanoparticles significantly similar to the use of either 5% HPMC or 1% HPMC-0.075% SDS, whereas CP was not effective due to its low swelling capacity. CCS/SSG enhanced steric-kinetic stabilization of the FNB suspensions owing to their high swelling capacity, viscosity enhancement, and physical barrier action. Overall, this study provides a mechanistic basis for a novel method of formulating surfactant-free drug nanosuspensions with co-milled superdisintegrants., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Although amorphous solid drug formulations may be advantageous for enhancing the bioavailability of poorly soluble active pharmaceutical ingredients, they exhibit poor physical stability and undergo recrystallization. To address this limitation, this study investigates stability issues associated with amorphous solids through analysis of the crystallization behavior for acetaminophen (APAP), known as a fast crystallizer, using a modified form of the Avrami equation that kinetically models both surface and bulk crystallization. It is found that surface-enhanced crystallization, occurring faster at the free surface than in the bulk, is the major impediment to the stability of amorphous APAP. It is hypothesized that a novel use of a dry-polymer-coating process referred to as mechanical-dry-polymer-coating may be used to inhibit surface crystallization and enhance stability. The proposed process, which is examined, simultaneously mills and coats amorphous solids with polymer, while avoiding solvents or solutions, which may otherwise cause stability or crystallization issues during coating. It is shown that solid dispersions of APAP (64% loading) with a small particle size (28 μm) could be prepared and coated with the polymer, carnauba wax, in a vibratory ball mill. The resulting amorphous solid was found to have excellent stability as a result of inhibition of surface crystallization., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Bioavailability of a poorly soluble drug can be improved by preparing a drug nanosuspension and subsequently drying it into nanocomposite microparticles (NCMPs). Unfortunately, drug nanoparticles aggregate during milling and drying, causing incomplete recovery and slow dissolution. The aim of this study is to investigate the impact of various classes of dispersants on drug dissolution from drug NCMPs, with the ultimate goal of enhancing the bioavailability of poorly water-soluble drugs via high drug nanoparticle loaded, surfactant-free NCMPs. Precursor suspensions of griseofulvin (GF, model drug) nanoparticles in the presence of various dispersants were prepared via wet stirred media milling and spray dried to form the NCMPs. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as a base-line stabilizer/dispersant during milling. Two swellable crosslinked polymers, croscarmellose sodium (CCS) and sodium starch glycolate (SSG), and a conventional soluble matrix former, Mannitol, were used in addition to HPC. Besides being used as-received, CCS was also wet co-milled with GF for two different durations to examine the impact of CCS particle size. Laser diffraction, scanning electron microscopy, powder X-ray diffraction (XRD), UV spectroscopy, NCMP redispersion and dissolution tests were used for characterization. The results show that incorporation of CCS/SSG, preferably wet-milled to a wide particle size distribution, into the spray-dried NCMPs resulted in fast release and dispersion of drug nanoparticle clusters. The swellable dispersants were superior to Mannitol in dissolution enhancement, and could achieve fast release comparable to SDS, demonstrating the feasibility of spray drying to prepare high drug-loaded, surfactant-free nanocomposites.

A major challenge in achieving size stability for relatively high concentration of fine particles from poorly water-soluble drug fenofibrate (FNB) is addressed through T-mixing based liquid antisolvent precipitation in the presence of ultrasonication and judicious use of stabilizers. Multiple stabilizers were screened in a batch mode prior to their continuous formation via T-mixing. In both cases, the stable suspensions maintained their size after 2 days of storage at room temperature, with the smallest particle size of d50: ∼1.2 µm was achieved through a combination of HPMC with SDS or PF-68. The influence of processing parameters, such as sonication energy, sonication probe insert depth and solvent/antisolvent flow rate, on the particle size distribution (PSD) in T-mixing were investigated, to identify optimum processing conditions. Optimal operating and formulation conditions also allowed increase in the drug loading from 0.32% to 4% (w/v), while keeping the median size 2.5 µm. Interestingly, the primary particles observed in the SEM were spherical and under 100 nm in diameter, indicating agglomeration. It was shown that the stabilized particles could be centrifuged and did not show size growth upon resuspension, allowing for increase in the drug loading up to 27% (w/v), which is a significant novel outcome.

Purpose: To investigate the effect of dry coating the amount and type of silica on powder flowability enhancement using a comprehensive set of 19 pharmaceutical powders having different sizes, surface roughness, morphology, and aspect ratios, as well as assess flow predictability via Bond number estimated using a mechanistic multi-asperity particle contact model., Method: Particle size, shape, density, surface energy and area, SEM-based morphology, and FFC were assessed for all powders. Hydrophobic (R972P) or hydrophilic (A200) nano-silica were dry coated for each powder at 25%, 50%, and 100% surface area coverage (SAC). Flow predictability was assessed via particle size and Bond number., Results: Nearly maximal flow enhancement, one or more flow category, was observed for all powders at 50% SAC of either type of silica, equivalent to 1 wt% or less for both the hydrophobic R972P or hydrophilic A200, while R972P generally performed slightly better. Silica amount as SAC better helped understand the relative performance. The power-law relation between FFC and Bond number was observed., Conclusion: Significant flow enhancements were achieved at 50% SAC, validating previous models. Most uncoated very cohesive powders improved by two flow categories, attaining easy flow. Flowability could not be predicted for both the uncoated and dry coated powders via particle size alone. Prediction was significantly better using Bond number computed via the mechanistic multi-asperity particle contact model accounting for the particle size, surface energy, roughness, and the amount and type of silica. The widely accepted 200 nm surface roughness was not valid for most pharmaceutical powders., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ibuprofen micronization with dry coating is investigated to examine its influence on passivation/stabilization of high-surface-energy sites and reduced cohesion. A fluid energy mill was used to micronize ibuprofen particles down to 5-28 μm with or without simultaneous nanosilica coating. Powder flow property and dispersibility were characterized using FT4 powder tester and Rodos/Helos laser diffraction particle sizer. Surface energy was characterized using a next generation inverse gas chromatography instrument. Uncoated micronized ibuprofen showed an increased Lifshitz-van der Waals (LW) dispersion component of surface energy with increasing milling intensity. In contrast, dry-coated milled powders showed a significant reduction in the LW component, whereas physical mixture of uncoated micronized ibuprofen and silica exhibited no reduction in surface energy, indicating that dry coating is necessary for the passivation of high-energy sites of ibuprofen created during micronization. Surface energy of pure micronized ibuprofen was highly heterogeneous, whereas dry-coated ibuprofen had greatly reduced heterogeneity. Micronization with dry coating also improved flowability and bulk density as compared with pure active pharmaceutical ingredient micronization without coating, or just blending with silica. Overall, dry coating leads to decreased cohesion and improved flowability because of reduced LW dispersive component of surface energy and creating nanoscale surface roughness., (Copyright © 2013 Wiley Periodicals, Inc.)

Motivated by our recent study showing improved flow and dissolution rate of the active pharmaceutical ingredient (API) powders (20 μm) produced via simultaneous micronization and surface modification through continuous fluid energy milling (FEM) process, the performance of blends and direct compacted tablets with high drug loading is examined. Performance of 50 μm API powders dry coated without micronization is also considered for comparison. Blends of micronized, non-micronized, dry coated or uncoated API powders at 30, 60 and 70% drug loading, are examined. The results show that the blends containing dry coated API powders, even micronized ones, have excellent flowability and high bulk density compared to the blends containing uncoated API, which are required for direct compaction. As the drug loading increases, the difference between dry coated and uncoated blends is more pronounced, as seen in the proposed bulk density-FFC phase map. Dry coating led to improved tablet compactibility profiles, corresponding with the improvements in blend compressibility. The most significant advantage is in tablet dissolution where for all drug loadings, the t(80) for the tablets with dry coated APIs was well under 5 min, indicating that this approach can produce nearly instant release direct compacted tablets at high drug loadings., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This is the first attempt, to our knowledge, that aims to empirically quantify and characterize international patient flows to Turkey. A cross-sectional retrospective study was performed on consecutive patients seen at the International Services Department of a 209-bed private hospital in urban Turkey. Over six months, international patients represented 4 percent and 6 percent of all consultations and surgical procedures, respectively. Six hundred and fifty unique international patients received health care and represented 44 different countries. Among these 650 unique encounters, most patients originated from Bulgaria (37%), Romania (35%), Azerbaijan (6%), Iraq (3%) and Georgia (3%). International patients commonly required oncological (54%), surgical (13%) and neurological (7%) services. Although quantitative data on medical travel to Turkey is limited, significant patient flows exist from neighboring countries to Turkey.

The circumgalactic medium (CGM) is fed by galaxy outflows and accretion of intergalactic gas, but its mass, heavy element enrichment, and relation to galaxy properties are poorly constrained by observations. In a survey of the outskirts of 42 galaxies with the Cosmic Origins Spectrograph onboard the Hubble Space Telescope, we detected ubiquitous, large (150-kiloparsec) halos of ionized oxygen surrounding star-forming galaxies; we found much less ionized oxygen around galaxies with little or no star formation. This ionized CGM contains a substantial mass of heavy elements and gas, perhaps far exceeding the reservoirs of gas in the galaxies themselves. Our data indicate that it is a basic component of nearly all star-forming galaxies that is removed or transformed during the quenching of star formation and the transition to passive evolution.

Simultaneous micronization and surface modification of drug particles is considered in order to mitigate disadvantages of micronization, e.g., agglomeration, poor flowability, marginal increase in surface area and low bulk density. Particles of ibuprofen (102 μm), a model drug, pre-blended with hydrophilic nano-silica, are micronized down to 10 and 5 μm in a continuous fluid energy mill (FEM) to obtain fine surface modified particles. The solid feeding rate and the grinding pressure are shown as critical parameters for achieving the desired particle size and size distribution. The powder properties were characterized via SEM, laser scattering, powder rheometer with shear-cell, and dissolution test. Significant improvement in flow properties and dissolution rate was observed when micronization accompanied surface modification. Additionally, co-grinding with water-soluble polymer during micronization led to further increase in bulk density and more enhanced dissolution rate improvement, which is attributed to improved wettability. XRD, DSC and Raman were used to examine crystallinity, indicating minimal detectable physical transformation with FEM processed ibuprofen. The surface modified, micronized powders also showed improved dispersion, higher bulk densities (>0.4 g/ml), reduced electrostatic, and higher flowability (FFC ≥ 6) compared to just micronized powder (0.19 g/ml, FFC=1.0), indicating they may be used in high drug loaded formulations amenable to direct compression., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Using a high-resolution cosmological hydrodynamic simulation, we present a method to constrain extinction due to intergalactic gray dust based on the observed magnitudes of distant Type Ia supernovae. We apply several simple prescriptions to relate the intergalactic dust density to the gas density in the simulation, thereby obtaining dust extinctions that may be directly compared with the observed distribution of supernova magnitudes. Our analysis is sensitive to the spatial distribution of gray dust but is not dependent on its intrinsic properties, such as its opacity or grain size. We present an application of our technique to the supernova data of Perlmutter et al., who find that their high-redshift sample is approximately 0.2 mag fainter than the expectation for a nonaccelerating, low-density universe. We find that for gray dust to be responsible, it must be distributed quite smoothly (e.g., tracing intergalactic gas). More realistic dust distributions, such as dust tracing the metal density, are inconsistent with observations at the 1.5-2 sigma level. Upcoming observations and improved modeling of the dust distribution should lead to stronger constraints on intergalactic gray dust extinction.

The present work reviews the liquid antisolvent crystallization (LASC) to prepare the nanoparticle of pharmaceutical compounds to enhance their solubility, dissolution rate, and bioavailability. The application of ultrasound and additives is discussed to prepare the particles with narrow size distribution. The use of ionic liquid as an alternative to conventional organic solvent is presented. Herbal compounds, also known for low aqueous solubility and limited clinical application, have been crystalized by LASC and discussed here. The particle characteristics such as particle size and particle size distribution are interpreted in terms of supersaturation, nucleation, and growth phenomena. To overcome the disadvantage of batch crystallization, the scientific literature on continuous flow reactors is also reviewed. LASC in a microfluidic device is emerging as a promising technique. The different design of the microfluidic device and their application in LASC are discussed. The combination of the LASC technique with traditional techniques such as high-pressure homogenization and spray drying is presented. A comparison of product characteristics prepared by LASC and the supercritical CO 2 antisolvent method is discussed to show that LASC is an attractive and inexpensive alternative for nanoparticle preparation. One of the major strengths of this paper is a discussion on less-explored applications of LASC in pharmaceutical research to attract the attention of future researchers., (© 2022. Controlled Release Society.)

Purpose: Fine API agglomeration and its mitigation via particle engineering, i.e., dry coating, remains underexplored. The purpose was to investigate agglomeration before and after dry coating of fine cohesive APIs and impact on powder processability, i.e., flowability (FFC), bulk density (BD), and dissolution of BCS Class II drugs., Method: Ibuprofen (three sizes), fenofibrate, and griseofulvin (5-20 µm), before and after dry coating with varying amounts of hydrophobic (R972P) or hydrophilic (A200) nano- silica, were assessed for agglomeration, FFC, BD, surface energy, wettability, and dissolution. The granular Bond number (Bo g ), a dimensionless parameter, evaluated through material-sparing particle-scale measures and particle-contact models, was used to express relative powder cohesion., Results: Significant powder processability improvements after dry coating were observed: FFC increased by multiple flow regimes, BD increased by 25-100%, agglomerate ratio (AR) reduction by over an order of magnitude, and greatly enhanced API dissolution rate even with hydrophobic (R972P) silica coating. Scrutiny of particle-contact models revealed non-triviality in estimating API surface roughness, which was managed through the assessment of measured bulk properties. A power-law correlation was identified between AR and Bo g and subsequently, between AR and FFC & bulk density; AR below 5 ensured improved processability and dissolution., Conclusion: Agglomeration, an overlooked material-sparing measure for powder cohesiveness, was a key indicator of powder processability and dissolution. The significant agglomerate reduction was possible via dry coating with either silica type at adequate surface area coverage. Reduced agglomeration after dry coating also countered the adverse impact of increased surface hydrophobicity on dissolution., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The impact of dry coating on reduced API agglomeration remains underexplored. Therefore, this work quantified fine cohesive API agglomeration reduction through dry coating and its impact on enhanced blend uniformity and processability, i.e., flowability and bulk density of multi-component blends API loading as low as 1 wt%., Methods: The impact of dry coating with two different types and amounts of silica was assessed on cohesion, agglomeration, flowability, bulk density, wettability, and surface energy of fine milled ibuprofen (~ 10 µm). API agglomeration, measured using Gradis/QicPic employing gentler gravity-based dispersion, resulted in excellent size resolution. Multi-component blends with fine-sized excipients, selected for reduced segregation potential, were tested for bulk density, cohesion, flowability, and blend content uniformity. Tablets formed using these blends were tested for tensile strength and dissolution., Result: All dry coated ibuprofen powders exhibited dramatic agglomeration reduction, corroborated by corresponding decreased cohesion, unconfined yield strength, and improved flowability, regardless of the type and amount of silica coating. Their blends exhibited profound enhancement in flowability and bulk density even at low API loadings, as well as the content uniformity for the lowest drug loading. Moreover, hydrophobic silica coating improved drug dissolution rate without appreciably reducing tablet tensile strength., Conclusion: The dry coating based reduced agglomeration of fine APIs for all three low drug loadings improved overall blend properties (uniformity, flowability, API release rate) due to the synergistic impact of a minute amount of silica (0.007 wt %), potentially enabling direct compression tableting and aiding manufacturing of other forms of solid dosing., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Nanosuspensions have been used for enhancing the bioavailability of poorly soluble drugs. This study explores the temperature evolution during their preparation in a wet stirred media mill using a coupled experimental-enthalpy balance approach., Methods: Milling was performed at three levels of stirrer speed, bead loading, and bead sizes. Temperatures were recorded over time, then simulated using an enthalpy balance model by fitting the fraction of power converted to heat ξ. Moreover, initial and final power, ξ, and temperature profiles at 5 different test runs were predicted by power-law (PL) and machine learning (ML) approaches., Results: Heat generation was higher at the higher stirrer speed and bead loading/size, which was explained by the higher power consumption. Despite its simplicity with a single fitting parameter ξ, the enthalpy balance model fitted the temperature evolution well with root mean squared error (RMSE) of 0.40-2.34°C. PL and ML approaches provided decent predictions of the temperature profiles in the test runs, with RMSE of 0.93-4.17 and 1.00-2.17°C, respectively., Conclusions: We established the impact of milling parameters on heat generation-power and demonstrated the simulation-prediction capability of an enthalpy balance model when coupled to the PL-ML approaches., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Recent observations have found a large number of supermassive black holes already in place in the first few hundred million years after the Big Bang, many of which seem to be overmassive relative to their host galaxy stellar mass when compared with local relation 1-9 . Several different models have been proposed to explain these findings, ranging from heavy seeds to light seeds experiencing bursts of high accretion rate 10-16 . Yet, current datasets are unable to differentiate between these various scenarios. Here we report the detection, from the JADES survey, of broad Hα emission in a galaxy at z = 6.68, which traces a black hole with a mass of about 4 × 10 8 M ⊙ and accreting at a rate of only 0.02 times the Eddington limit. The black hole to host galaxy stellar mass ratio is about 0.4-that is, about 1,000 times above the local relation-whereas the system is closer to the local relations in terms of dynamical mass and velocity dispersion of the host galaxy. This object is most likely an indication of a much larger population of dormant black holes around the epoch of reionization. Its properties are consistent with scenarios in which short bursts of super-Eddington accretion have resulted in black hole overgrowth and massive gas expulsion from the accretion disk; in between bursts, black holes spend most of their life in a dormant state., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

We characterize luminosity components of Ultra/Luminous Infrared Galaxies (U/LIRGs) in multi-wavelength from the X-ray to far-infrared. A set of 63 AGN U/LIRGs was selected where these galaxies are powered by a central active galactic nucleus (AGN). Utilizing the X-CIGALE code, SEDs for these galaxies are carried out where their SEDs are fitted with observations. Accordingly, the physical parameters such as the stellar mass, the dust-to-gas mass ratio, and the star formation rate are calculated. The total luminosity and its decomposed components (stellar, AGN, X-ray) are also calculated. We characterized these luminosities in relative to the intrinsic luminosity and in relative to each other. As a function of the stellar mass, these luminosities reveal an increase with different correlation coefficients, showing a strong correlation. In correlation with the intrinsic AGN power, the stellar, AGN, and X-ray luminosities are strongly correlates in their variation to the intrinsic AGN luminosity, showing stronger correlations of AGN, and X-ray luminosities than those of the stellar one. In relationships between various luminosity components, both the stellar and X-ray luminosities reveal strong correlations with the AGN luminosity. On the other hand, the X-ray luminosity varies strongly with the stellar luminosity and moderately with IR luminosity. Compared to obscured AGN galaxies, both the stellar and AGN luminosities similarly vary with increasing the intrinsic power of the active nucleus but for obscured AGN they are faster in their variation than that of U/LIRG. These correlations may offer valuable insights to understand the physical properties and their relationships through the evolution of U/LIRGs., (© 2024. The Author(s).)

The granulation of traditional Chinese medicine (TCM) has attracted widespread attention, there is limited research on the high shear wet granulation (HSWG) and wetting mechanisms of sticky TCM powders, which profoundly impact the granule size distribution (GSD). Here we investigate the wetting mechanism of binders and the influence of various parameters on the GSD of HSWG and establish a GSD prediction model. Permeability and contact angle experiments combined with molecular dynamics (MD) simulations were used to explore the wetting mechanism of hydroalcoholic solutions with TCM powder. Machine learning (ML) was employed to build a GSD prediction model, feature importance explained the influence of features on the predictive performance of the model, and correlation analysis was used to assess the influence of various parameters on GSD. The results show that water increases powder viscosity, forming high-viscosity aggregates, while ethanol primarily acted as a wetting agent. The contact angle of water on the powder bed was the largest and decreased with an increase in ethanol concentration. Extreme Gradient Boosting (XGBoost) outperformed other models in overall prediction accuracy in GSD prediction, the binder had the greatest impact on the predictions and GSD, adjusting the amount and concentration of adhesive can control the adhesion and growth of granules while the impeller speed had the least influence on granulation. The study elucidates the wetting mechanism and provides a GSD prediction model, along with the impact of material properties, formulation, and process parameters obtained, aiding the intelligent manufacturing and formulation development of TMC., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Creative block is a familiar foe to any who attempt to create and is especially related to "writers block". While significant effort has been focused on developing methods to break such blocks, it remains an active challenge. Here, we focus on the role of semantic memory structure in driving creative block, by having people get "stuck" in a certain part of their semantic memory network. We directly examine whether we can "pull out" a participant from where they got "stuck" in their semantic memory, breaking their creative impasse. Our Associative Creativity Sparker (ACS) is a cognitive network science-based online tool that aims to spark creative ideas and break creative impasse: Once a participant runs out of ideas in a creative idea generation task, word recommendations are suggested to prime new ideas. These word recommendations are either towards or away from previous ideas, as well as close or far from the target object, based on a conceptual space extracted from the participants responses using online text analysis. In Study 1, 121 participants use the ACS to generate creative alternative uses for five different objects and completed creativity and Gf tasks. In Study 2, we repeat the design of Study 1, but further examine the impact of writing experience on the ACS, by examining 120 novice and 120 experienced writers. Across both studies, our results indicate that the location of word recommendations affects the fluency and originality of one's ideas, and that novice and experienced writers differently benefit from these word recommendations., (© 2024. The Author(s).)

The Cosmic Gems arc is among the brightest and highly magnified galaxies observed at redshift z ≈ 10.2 (ref.  1 ). However, it is an intrinsically ultraviolet faint galaxy, in the range of those now thought to drive the reionization of the Universe 2-4 . Hitherto the smallest features resolved in a galaxy at a comparable redshift are between a few hundreds and a few tens of parsecs (pc) 5,6 . Here we report JWST observations of the Cosmic Gems. The light of the galaxy is resolved into five star clusters located in a region smaller than 70 pc. They exhibit minimal dust attenuation and low metallicity, ages younger than 50 Myr and intrinsic masses of about 10 6 M ⊙ . Their lensing-corrected sizes are approximately 1 pc, resulting in stellar surface densities near 10 5 M ⊙  pc -2 , three orders of magnitude higher than typical young star clusters in the local Universe 7 . Despite the uncertainties inherent to the lensing model, they are consistent with being gravitationally bound stellar systems, that is, proto-globular clusters. We conclude that star cluster formation and feedback likely contributed to shaping the properties of galaxies during the epoch of reionization., (© 2024. The Author(s).)

Purpose: We aimed to evaluate the feasibility of cross-linked polystyrene (CPS)-yttrium-stabilized zirconia (YSZ) bead mixtures as a novel optimization approach for fast, effective production of drug nanosuspensions during wet stirred media milling (WSMM)., Methods: Aqueous suspensions of 10% fenofibrate (FNB, drug), 7.5% HPC-L, and 0.05% SDS were wet-milled at 3000-4000 rpm and 35%-50% volumetric loading of CPS:YSZ bead mixtures (CPS:YSZ 0:1-1:0 v:v). Laser diffraction, SEM, viscometry, DSC, and XRPD were used for characterization. An n th -order model described the breakage kinetics, while a microhydrodynamic model allowed us to gain insights into the impact of bead materials., Results: CPS beads achieved the lowest specific power consumption, whereas YSZ beads led to the fastest breakage. Breakage followed second-order kinetics. Optimum conditions were identified as 3000 rpm and 50% loading of 0.5:0.5 v/v CPS:YSZ mixture from energy-cycle time-heat dissipation perspectives. The microhydrodynamic model suggests that YSZ beads experienced more energetic/forceful collisions with smaller contact area as compared with CPS beads owing to the higher density-elastic modulus of the former., Conclusions: We demonstrated the feasibility of CPS-YSZ bead mixtures and rationalized its optimal use in WSMM through their modulation of breakage kinetics, energy utilization, and heat dissipation., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A radioimmunoassay (RIA) was developed for the quantification of caffeine in saliva. The mean salivary caffeine level for this sample of 40 full-term, AGA, healthy 1-2 day old human neonates was consistent with levels reported in previous studies. Salivary caffeine was significantly correlated with the number of state changes and startles observed during administration of the Brazelton Neonatal Behavior Assessment Scale. There was also a nonsignificant trend correlating salivary caffeine with visual orienting and consolability.

Neurobehavioral evaluation of the high-risk neonate represents an important advance in early detection of behavioral anomalies which may give rise to later neuropsychological sequelae. In the present study neonates comprising three diagnostic categories (i.e., respiratory distressed, seizure-disordered, normals) were evaluated with the Brazelton Neonatal Behavior Assessment Scale (BNBAS) to determine the extent to which differences in neurobehavioral organization could be detected with the scale, and how they were related to diagnostic classification. Average conceptional age at testing for the three groups was within the range usually considered full term: e.g., 38.81 weeks (respiratory distressed), 40.18 weeks (normal healthy) and 42.54 weeks (seizure disorder). Infants who had been diagnosed with neonatal seizures exhibited consistently less optimal behavior than did either of the other two groups. Infants with respiratory distress and normal controls did not differ significantly on most summary measures of neurobehavioral organization scored with the BNBAS. The study offers support for the discriminative validity of the BNBAS and its potential usefulness in the assessment of clinically ill newborns.

After an initial grounding discussion, in which the linear mass-sectional population balance is described, and models for reducing the number of its parameters are discussed, this modeling approach is applied to a wide range of processes including batch mills, single-pass continuous mills, mills in series, mills with recycle, milling circuits including classification, and recycled-batch milling. The linearity of the model allows its straightforward inclusion in calculations for all of these processes. The sensitivity of the model to its inputs (order of rate kernel in size, fragment distribution) is explored for batch operations. Then, the effects of key continuous process design variables are explored including the (a) number of mill passes in pendulum milling (mills in series), (b) classifier properties in circuits with classification, and (c) ratio of feed tank-to-mill residence time in recycled-batch operations.

Drug nanocrystals have been used for a wide range of drug delivery platforms in the pharmaceutical industry, especially for bioavailability enhancement of poorly water-soluble drugs. Wet stirred media milling (WSMM) is the most widely used process for producing dense, stable suspensions of drug nanoparticles, also referred to as nanosuspensions. Despite a plethora of review papers on the production and applications of drug nanosuspensions, modeling of WSMM has not been thoroughly covered in any review paper before. The aim of this review paper is to briefly expose the pharmaceutical scientists and engineers to various modeling approaches, mostly mechanistic, including computational fluid dynamics (CFD), discrete element method (DEM), population balance modeling (PBM), coupled methods, the stress intensity-number model (SI-SN model), and the microhydrodynamic (MHD) model with a main focus on the MHD model for studying the WSMM process. A total of 71 studies, 30 on drugs and 41 on other materials, were reviewed. Analysis of the pharmaceutics literature reveals that WSMM modeling is largely based on empirical, statistically based modeling approaches, and mechanistic modeling could help pharmaceutical engineers develop a fundamental process understanding. After a review of the salient features and various pros-cons of each modeling approach, recent advances in microhydrodynamic modeling and process insights gained therefrom were highlighted. The SI-SN and MHD models were analyzed and critiqued objectively. Finally, the review points out potential research directions such as more mechanistic and accurate CFD-DEM-PBM simulations and the coupling of the MHD-PBM models with the CFD.

Nylon, a widely-used high-performance thermoplastic, boasts exceptional durability and resistance to various solvents and weak acids, making it indispensable across diverse applications. However, its nonbiodegradable nature has led to alarming environmental pollution in land and oceans. Chemical recycling to monomers (CRM) stands as a crucial strategy for establishing a circular plastic economy, but the CRM of nylon remains largely unexplored. Herein, we introduce the bridged bicyclic lactam 5-azabicyclo[2.2.1]octan-6-one (5/6-LM), evolved from δ-valerolactam and pyrrolidone, to solve the trade-off in depolymerizability and performance. Notably, 5/6-LM exhibits nearly 95 % conversion in mild polymerization conditions and efficient depolymerization catalyzed by lewis acids. This compound is synthetically accessible from commercially available chemicals in a single step at room temperature, demonstrating high efficiency and scalability up to 50 g in laboratory. Furthermore, the resulting polyamide displays remarkable attributes including high crystallinity and thermostability up to 283 °C, significantly broadening the scope of chemically recyclable nylons., (© 2024 Wiley‐VCH GmbH.)

Local and low-redshift (z < 3) galaxies are known to broadly follow a bimodal distribution: actively star-forming galaxies with relatively stable star-formation rates and passive systems. These two populations are connected by galaxies in relatively slow transition. By contrast, theory predicts that star formation was stochastic at early cosmic times and in low-mass systems 1-4 . These galaxies transitioned rapidly between starburst episodes and phases of suppressed star formation, potentially even causing temporary quiescence-so-called mini-quenching events 5,6 . However, the regime of star-formation burstiness is observationally highly unconstrained. Directly observing mini-quenched galaxies in the primordial Universe is therefore of utmost importance to constrain models of galaxy formation and transformation 7,8 . Early quenched galaxies have been identified out to redshift z < 5 (refs.  9-12 ) and these are all found to be massive (M ⋆  > 10 10  M ⊙ ) and relatively old. Here we report a (mini-)quenched galaxy at z = 7.3, when the Universe was only 700 Myr old. The JWST/NIRSpec spectrum is very blue (U-V = 0.16 ± 0.03 mag) but exhibits a Balmer break and no nebular emission lines. The galaxy experienced a short starburst followed by rapid quenching; its stellar mass (4-6 × 10 8  M ⊙ ) falls in a range that is sensitive to various feedback mechanisms, which can result in perhaps only temporary quenching., (© 2024. The Author(s).)

Tributyl citrate (TBC) plays a crucial role as a plasticizer, enhancing the flexibility of polymers such as polyvinyl chloride. Its biodegradability and non-toxic nature contribute to eco-friendly appeal, making it a preferred additive in diverse industries, including food packaging, medical devices, toys, and consumer goods. Herein, a method for the synthesis of TBC using inexpensive Brønsted acidic protic ionic liquids (ILs) in a two-phase reaction system is presented. The esterification process is carried out with high yield (>99 %), selectivity (up to 98 %) and short reaction time of 2 h. The catalyst in the form of IL shows excellent performance and stability, desirable for industrial applications., (© 2024 Wiley‐VCH GmbH.)

Purpose: Dalbavancin, approved in 2014 for Gram-positive acute bacterial skin and skin structure infections (ABSSSI), has pharmacokinetics enabling treatment with one or two doses. Dalbavancin might be useful in outpatient parenteral antibiotic therapy (OPAT) of deep-seated infections, otherwise requiring inpatient admission. We documented our experience with pragmatic dalbavancin use to assess its effectiveness for varied indications, on- and off-label, as primary or sequential consolidation therapy., Methods: Patients prescribed dalbavancin between 1 December 2021 and 1 October 2022 were screened for demographics of age, sex, Charlson comorbidity index (CCI), allergies, pathogens, doses of dalbavancin, other antibiotics administered and surgery. Where available, infection markers were recorded. The primary outcome was a cure at the end of treatment. Secondary outcomes included any adverse events and for those with treatment failures, response to salvage antibiotics., Results: Sixty-seven per cent of patients were cured. Cure rates by indication were 93% for ABSSSI, 100% for bacteraemia, 90% for acute osteomyelitis, 0% for chronic osteomyelitis, 75% for native joint septic arthritis and 33% for prosthetic joint infection. Most bone and joint infections that were not cured did not have source control, and the goal of treatment was suppressive. Successful suppression rates were greater at 48% for chronic osteomyelitis and 66% for prosthetic joint infections. Adverse events occurred in 14 of 102 patients., Conclusion: This report adds to clinical experience with dalbavancin for off-label indications whilst further validating its role in ABSSSI. Dalbavancin as primary therapy in deep-seated infections merits investigation in formal clinical trials., (© 2024. Crown.)

The formation of galaxies by gradual hierarchical co-assembly of baryons and cold dark matter halos is a fundamental paradigm underpinning modern astrophysics 1,2 and predicts a strong decline in the number of massive galaxies at early cosmic times 3-5 . Extremely massive quiescent galaxies (stellar masses of more than 10 11  M ⊙ ) have now been observed as early as 1-2 billion years after the Big Bang 6-13 . These galaxies are extremely constraining on theoretical models, as they had formed 300-500 Myr earlier, and only some models can form massive galaxies this early 12,14 . Here we report on the spectroscopic observations with the JWST of a massive quiescent galaxy ZF-UDS-7329 at redshift 3.205 ± 0.005. It has eluded deep ground-based spectroscopy 8 , it is significantly redder than is typical and its spectrum reveals features typical of much older stellar populations. Detailed modelling shows that its stellar population formed around 1.5 billion years earlier in time (z ≈ 11) at an epoch when dark matter halos of sufficient hosting mass had not yet assembled in the standard scenario 4,5 . This observation may indicate the presence of undetected populations of early galaxies and the possibility of significant gaps in our understanding of early stellar populations, galaxy formation and the nature of dark matter., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The identification of sources driving cosmic reionization, a major phase transition from neutral hydrogen to ionized plasma around 600-800 Myr after the Big Bang 1-3 , has been a matter of debate 4 . Some models suggest that high ionizing emissivity and escape fractions (f esc ) from quasars support their role in driving cosmic reionization 5,6 . Others propose that the high f esc values from bright galaxies generate sufficient ionizing radiation to drive this process 7 . Finally, a few studies suggest that the number density of faint galaxies, when combined with a stellar-mass-dependent model of ionizing efficiency and f esc , can effectively dominate cosmic reionization 8,9 . However, so far, comprehensive spectroscopic studies of low-mass galaxies have not been done because of their extreme faintness. Here we report an analysis of eight ultra-faint galaxies (in a very small field) during the epoch of reionization with absolute magnitudes between M UV  ≈ -17 mag and -15 mag (down to 0.005L ⋆ (refs.  10,11 )). We find that faint galaxies during the first thousand million years of the Universe produce ionizing photons with log[ξ ion  (Hz erg -1 )] = 25.80 ± 0.14, a factor of 4 higher than commonly assumed values 12 . If this field is representative of the large-scale distribution of faint galaxies, the rate of ionizing photons exceeds that needed for reionization, even for escape fractions of the order of 5%., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

During the first 500 million years of cosmic history, the first stars and galaxies formed, seeding the Universe with heavy elements and eventually reionizing the intergalactic medium 1-3 . Observations with the James Webb Space Telescope (JWST) have uncovered a surprisingly high abundance of candidates for early star-forming galaxies, with distances (redshifts, z), estimated from multiband photometry, as large as z ≈ 16, far beyond pre-JWST limits 4-9 . Although such photometric redshifts are generally robust, they can suffer from degeneracies and occasionally catastrophic errors. Spectroscopic measurements are required to validate these sources and to reliably quantify physical properties that can constrain galaxy formation models and cosmology 10 . Here we present JWST spectroscopy that confirms redshifts for two very luminous galaxies with z > 11, and also demonstrates that another candidate with suggested z ≈ 16 instead has z = 4.9, with an unusual combination of nebular line emission and dust reddening that mimics the colours expected for much more distant objects. These results reinforce evidence for the early, rapid formation of remarkably luminous galaxies while also highlighting the necessity of spectroscopic verification. The large abundance of bright, early galaxies may indicate shortcomings in current galaxy formation models or deviations from physical properties (such as the stellar initial mass function) that are generally believed to hold at later times., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)