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The present work reports Fick diffusion coefficients D11and thermal diffusivities aof binary liquid mixtures containing n-heptane, 2,3-dimethylpentane, methylcyclohexane, toluene, n-decane, butylcyclohexane, butylbenzene, naphthalene, cis- or trans-decahydronaphthalene, 1,2,3,4-tetrahydronaphthalene, diphenylmethane, dicyclohexylmethane, ortho-benzyltoluene, or ortho-perhydrobenzyltoluene at equimolar composition determined by the shadowgraph method. Experiments were performed in the compressed liquid phase at temperatures Tfrom (298 to 473) K and pressures p≈ (0.1 to 1.4) MPa as well as at pfrom (0.1 to 30) MPa and T= 298 K or, studying a mixture of naphthalene and toluene, T= 373 K. D11and awere determined with average expanded experimental uncertainties (k= 2) of (13 and 8.0)% and their relationships to the molecular characteristics of the mixture components were analyzed. For D11, dependencies on the molar mass, viscosity, and molecular structures such as branching, alkane (side) chain length, stereoisomerism, and aromatic or aliphatic rings of the mixture components were identified. Regarding a, only influences related to stereoisomerism as well as diphenylmethane, ortho-benzyltoluene, and their hydrogenated species were found. Additionally, the T-dependent D11and adata were compared to corresponding data from the literature.

Sapphire fiber can withstand temperatures of around 2000 °C, but it is multimoded, giving poor precision sensors. We have demonstrated a single-mode sapphire fiber Bragg grating temperature sensor operating up to 1200 °C. A single-mode sapphire fiber was formed by writing a depressed cladding waveguide along the length of a 100-μm diameter sapphire fiber using a femtosecond laser. A second-order Bragg grating sensor was inscribed within the waveguide, achieving a reflectivity of >90% and a narrow bandwidth of <0.5 nm. The single-mode sapphire fiber was fusion spliced to standard silica single-mode fiber. The sensor was vibration-tested over a 10 Hz to 30 kHz range with 30 μm displacement, resulting in minimal Bragg wavelength variation of <30 pm standard deviation. The sensor was furnace-tested to 1200 °C, showing ±0.08% repeatability above 1000 °C. This demonstrates the high precision sensing capability of single-mode sapphire fiber Bragg grating sensors with end-to-end single mode interrogation.

Liver cyst infections often necessitate long-term hospital admission and are associated with considerable morbidity and mortality. We conducted a modified Delphi study to reach expert consensus for a clinical decision framework. The expert panel consisted of 24 medical specialists, including 12 hepatologists, from nine countries across Europe, North America, and Asia. The Delphi had three rounds. The first round (response rate 21/24 [88%]) was an online survey with questions constructed from literature review and expert opinion, in which experts were asked about their management preferences and rated possible management strategies for seven clinical scenarios. Experts also rated 14 clinical decision-making items for relevancy and defined treatment outcomes. During the second round (response rate 13/24 [54%]), items that did not reach consensus and newly suggested themes were discussed in an online panel meeting. In the third round (response rate 16/24 [67%]), experts voted on definitions and management strategies using an online survey based on previous answers. Consensus was predefined as a vote threshold of at least 75%. We identified five subclassifications of liver cyst infection according to cyst phenotypes and patient immune status and consensus on episode definitions (new, persistent, and recurrent) and criteria for treatment success or failure was reached. The experts agreed that fever and elevated C-reactive protein are pivotal decision-making items for initiating and evaluating the management of liver cyst infections. Consensus was reached on 26 management statements for patients with liver cyst infections across multiple clinical scenarios, including two treatment algorithms, which were merged into one after comments. We provide a clinical decision framework for physicians managing patients with liver cyst infections. This framework will facilitate uniformity in the management of liver cyst infections and can constitute the basis for the development of future guidelines.

Additive manufacturing (AM) is increasingly being used to fabricate end-use and high-value-added parts in a range of industries. AM’s ability to create complex geometries and vary the internal composition of a part has enabled the design of many novel devices, including radio frequency (RF) devices that rely on the spatial variation of electromagnetic (EM) properties. However, current AM processes for fabricating complex parts are typically run without any part monitoring or online feedback control, and as a result, the printed parts may be compromised by defects or have poor tolerances. Manufacturing parts in this way also requires extra quality testing since there is no knowledge of their interior quality. For these reasons, introducing process monitoring and corrective action to the AM process has become an important area of research as AM is being used to create safety-critical parts. This work proposes a control algorithm to enable closed-loop control of an EM property, specifically dielectric permittivity, within a print using a fused filament fabrication (FFF) printer. The control system used a split-ring resonator (SRR) to measure the permittivity of printed thermoplastic, and the control action was applied by updating the printed infill density layer to layer. This control system was tested by printing a proof-of-concept graded-index (GRIN) lens with spatially varying permittivity through the lens’ length. The results demonstrate the ability of the controller to follow a constantly varying reference signal, indicating the potential of closed-loop control for improved fabrication of functional RF devices that depend on precise variations in relative permittivity.

Our systematic review highlights that multiparametric PAI score assessment is a consistent tool with high sensitivity and specificity for prenatal prediction for placenta accreta spectrum (PAS) in high‐risk population with anterior placenta previa or low‐lying placenta and prior cesarean deliveries. A systematic search was conducted on November 1, 2022, of MEDLINE via PubMed, Scopus, Web of Science Core Collection, Cochrane Library, and Google Scholar to identify relevant studies (PROSPERO ID # CRD42022368211). A total of 11 articles met our inclusion criteria, representing the data of a total of 1,044 cases. Women with PAS had an increased mean PAI total score, compared to those without PAS. Limitations of the PAI are most studies were conducted in developing countries in high‐risk population which limit the global generalizability of findings. Heterogeneity of reported data did not allow to perform meta‐analysis.

We demonstrate the fabrication and optimization of waveguide Bragg gratings on single-crystal sapphire substrates using femtosecond laser direct writing. The gratings are fabricated using modulated bursts and are embedded inside single-mode depressed cladding waveguides. Through design optimization, and fabrication parameter tuning, a depressed cladding waveguide with a loss of ∼0.8 dB/cm and a Bragg grating with a reflectivity of higher than 90% in the telecommunications wavelength band are demonstrated. The waveguide Bragg grating exhibits stable thermal properties under annealing at 1200 °C. A sampled grating and a grating array are also demonstrated, showing the potential for more complex grating designs.

Viral testing and treatments such as systemic steroids and inhaled corticosteroids are low-value care for routine bronchiolitis. We sought to determine the impact of the COVID-19 pandemic on low-value care in young children with bronchiolitis.This was a retrospective, cross-sectional study using the Pediatric Health Information Systems database. We included children <2 years seen in a pediatric emergency department for bronchiolitis. We selected a priori 3 study periods: September 2018 to February 2020 (prepandemic), March 2020 to August 2022 (early pandemic), and September 2022 to January 2023 (late pandemic). Low-value care included respiratory syncytial virus testing, chest radiography, albuterol, or corticosteroids and was compared across the 3 time periods.At least 1 element of low-value care was provided in 45%, 47%, and 44% of encounters in the prepandemic, early pandemic, and late pandemic periods, respectively. There was little variation in the use of albuterol and chest radiography across time periods and a slight increase in systemic corticosteroid use from prepandemic to early and late pandemic groups. Viral testing increased from 36% prepandemic to 65% early pandemic and 67% late pandemic, which appeared to be driven by SARS-CoV-2 testing and combination viral testing.There was no clinically significant change in low-value care for bronchiolitis during the pandemic. Because of SARS-CoV-2 testing, however, overall frequency of viral testing increased dramatically over time. This marked increase in overall viral testing should be taken into consideration for future quality improvement efforts.

Nanosizing drug crystals has emerged as a successful approach to enabling oral bioavailability, as increasing drug crystal surface area improves dissolution kinetics and effective solubility. Recently, bottom-up methods have been developed to directly assemble nanosized crystals by leveraging polymer and surfactant excipients during crystallization to control crystal size, morphology, and structure. However, while significant research has investigated how polymers and other single additives inhibit or promote crystallization in pharmaceutical systems, there is little work studying the mechanistic interactions of multiple excipients on drug crystal structure and the extent of crystallinity, which can influence formulation performance. This study explores how the structure and crystallinity of a model hydrophobic drug crystal, fenofibrate, change as a result of competitive interfacial chemisorption between common nonionic surfactants (polysorbate 80 and sorbitan monooleate) and a surface-active polymer excipient (methylcellulose). Classical molecular dynamics simulations highlight how key intermolecular interactions, including surfactant–polymer complexation and surfactant screening of the crystal surface, modify the resulting crystal structure. In parallel, experiments generating drug nanocrystals in hydrogel thin films validate that drug crystallinity increases with an increasing weight fraction of surfactant. Simulation results reveal a connection between accelerated dynamics in the bulk crystal and the experimentally measured extent of crystallinity. To our knowledge, these are the first simulations that directly characterize structural changes in a drug crystal as a result of excipient surface composition and relate the experimental extent of crystallinity to structural changes in the molecular crystal. Our approach provides a mechanistic understanding of crystallinity in nanocrystallization, which can expand the range of orally deliverable small molecule therapies.

In this experimental study, we combine drop impact into porous media and onto a single fiber to study drop impact into fiber arrays inspired by mammalian fur coats. In our 3D-printed arrays, we vary the packing density, fiber alignment, strand cross-section, and wettability. Drops impact fibers fixed at both ends, penetrating over short periods of time by momentum and laterally spreading throughout the array. Using image analysis, we measure penetration depth and wetted width into the array. Impact Weber number and intrinsic porosity define penetration, retraction, and rebound regimes. On average, at an impact Weber number of ≈80, staggered fibers reduce penetration by 24% in hydrophilic fibers and 34% in hydrophobic fibers, and the penetration reduction percentage is expected to increase with increasing Weber number. Our results indicate that as density grows toward the density of mammalian pelts, penetration will reach a maximum value independent of drop impact velocity, thereby providing an effective rain barrier. Hydrophilicity at the densities we test, 50–150 strands/cm2, aids fiber array resistance to dynamic penetration by impacting drops through the promotion of lateral drop spreading and inhibition of drop fragmentation. Conversely, hydrophobic fibers best resist low-speed wicking. The fraction of a drop that infiltrates hydrophilic and hydrophobic fibers is nearly identical for a fixed Weber number because lateral spreading restricts the penetration depth into hydrophilic fibers but does not restrict mass infiltration. Above a critical Weber number, the entire drop mass penetrates fiber arrays regardless of strand wettability.

It is important to have reliable information on the presence/absence, population structure, and density of animals across their natural range. Detecting small organisms, however, such as the Nearctic tree trunk sheetweaver spider Drapetisca alterandaChamberlin 1909 (Araneae: Linyphiidae), presents challenges due to its diminutive size and cryptic nature. We used a capture/recapture study to determine the detection and recapture probabilities of this spider using a standard beat sheet technique adopted for surveying tree trunks. Spiders were released on 3 different tree species that provided a range of microhabitats, including variable bark surface area and furrow depth/width. Microhabitat features played a small role in the timing of spider recapture (i.e., slower rate of recapture as furrowing increased). However, our results demonstrated 100% detection across replicate experiments and individual recapture probabilities exceeding 90% in most situations, with no significant differences in recapture observed among tree species and with respect to tree circumference. Furthermore, we show that most spiders could be recaptured within 2 sampling revolutions around the tree trunk, and there was no difference in the probability of collecting male and female spiders (although they differ markedly in size). Finally, we found no difference among brushers, supporting the idea that this method is replicable across collectors and studies. Collectively, we establish confidence in the ecological knowledge obtained with this technique and encourage its application with similar species and systems.

The purpose of this study was to define the risk and outcomes of esophageal varices in adults with Fontan palliation and liver cirrhosis undergoing esophagogastroduodenoscopy (EGD).

In this work, we demonstrate the use of two-photon polymerization direct laser writing in the production of continuously tuneable optical vortex beam (OV) generators in a liquid crystal (LC) layer sandwiched between glass substrates. Results are presented that show how an OV generator can be inscribed into a 20 μm-thick LC layer and how the order of the OV beam can be tuned with the application of a voltage. Importantly, only a single pair of electrodes is needed to tune the order of the vortex as the required phase profile is generated through the 3D structuring of the polymer network using the laser writing process. Following the design and fabrication of the LC-OV generator, a Mach–Zehnder interferometer is subsequently employed, in conjunction with polarizing optical microscopy, to characterize the devices to confirm the generation of OVs of different orders and to determine the corresponding chirality. The paper concludes by considering whether these LC-OV generators can function at a range of different operation wavelengths. Such devices would be of potential importance in applications ranging from optical communications to quantum physics.

Nemtabrutinib (MK-1026) is a novel oral Bruton’s tyrosine kinase (BTK) inhibitor for treatment of B-cell cancers. An initial synthetic supply route to generate ketone 3relied on the generation of a highly reactive transient intermediate and the use of n-butyllithium. Cryogenic temperatures (−60 °C) were also required to achieve a modest 61% yield, with one major impurity, resulting from dehalogenation, accounting for the majority of the mass balance. An alternative process was developed to increase the yield and decrease the dependence on cryogenic temperatures, and this advancement was critical to the long-term robustness of the commercial process. Key advancements included performing the requisite deprotonation and metalation steps sequentially and performing the metalation and quench steps in flow. The final flow process was rapidly scaled from grams to tens of kilograms and has been successfully executed in a production facility.

In one of the two penultimate steps in the commercial route to nemtabrutinib, a ketone intermediate is formed from 7-bromo-6-chloro-7-deazapurine and methyl 2-chloro-4-phenoxybenzoate in a series of reactions mediated by methyllithium and n-butyllithium. Flow chemistry was identified in development as a useful tool for safe and efficient scale-up for two of these reactions while minimizing the formation of unwanted impurities. Here, we present the first pilot-scale implementation of the process where a tubular flow reactor was employed to produce multiple kilograms of the ketone intermediate. Practical considerations for large-scale operations are discussed, including operation at low temperatures around −30 °C, stable and consistent control of flow rates, and planning for the prevention of and recovery from upset scenarios. Careful design and construction of equipment and procedures allowed for the successful execution of five pilot-scale batches with consistent yield and product quality to produce material needed for clinical development. Across the campaign, average isolated yield for the process was approximately 65%, with an average purity of 99.9% by weight. Also presented are the findings from a series of large-scale flow experiments, where temperature, residence time, and reaction stoichiometry were simultaneously varied to assess process robustness. In these experiments, n-butyllithium stoichiometry was found to have the greatest impact on reaction yield, as measured by product LC area percent. Additionally, the process impurities studied were each sensitive to a different combination of the varied parameters. Learnings from this pilot campaign were critical to guide future development efforts en route to a potential commercial supply of nemtabrutinib.

Thirteen American Hereford cattle were reported blind with presumed onset when ~12-mo-old. All blind cattle shared a common ancestor through both the maternal and paternal pedigrees, suggesting a recessive genetic origin. Given the pedigree relationships and novel phenotype, we characterized the ophthalmo-pathologic changes associated with blindness and identified the responsible gene variant. Ophthalmologic examinations of 5 blind cattle revealed retinal degeneration. Histologically, 2 blind cattle had loss of the retinal photoreceptor layer. Whole-genome sequencing (WGS) of 7 blind cattle and 9 unaffected relatives revealed a 1-bp frameshift deletion in ceroid lipofuscinosis neuronal 3 (CLN3; chr25 g.26043843del) for which the blind cattle were homozygous and their parents heterozygous. The identified variant in exon 16 of 17 is predicted to truncate the encoded protein (p. Pro369Argfs*8) battenin, which is involved in lysosomal function necessary for photoreceptor layer maintenance. Of 462 cattle genotyped, only blind cattle were homozygous for the deletion. A query of WGS data of > 5,800 animals further revealed that the variant was only observed in related Hereford cattle. Mutations in CLN3are associated with human juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease, which results in early-onset retinal degeneration and lesions similar to those observed in our cases. Our data support the frameshift variant of CLN3as causative of blindness in these Hereford cattle, and provide additional evidence of the role of this gene in retinal lesions, possibly as a model for human non-syndromic JNCL.

AbstractObjective:To learn about the perceptions of healthcare personnel (HCP) on the barriers they encounter when performing infection prevention and control (IPC) practices in labor and delivery to help inform future IPC resources tailored to this setting.Design:Qualitative focus groups.Setting:Labor and delivery units in acute-care settings.Participants:A convenience sample of labor and delivery HCP attending the Infectious Diseases Society for Obstetrics and Gynecology 2022 Annual Meeting.Methods:Two focus groups, each lasting 45 minutes, were conducted by a team from the Centers for Disease Control and Prevention. A standardized script facilitated discussion around performing IPC practices during labor and delivery. Coding was performed by 3 reviewers using an immersion-crystallization technique.Results:In total, 18 conference attendees participated in the focus groups: 67% obstetrician-gynecologists, 17% infectious disease physicians, 11% medical students, and 6% an obstetric anesthesiologist. Participants described the difficulty of consistently performing IPC practices in this setting because they often respond to emergencies, are an entry point to the hospital, and frequently encounter bodily fluids. They also described that IPC training and education is not specific to labor and delivery, and personal protective equipment is difficult to locate when needed. Participants observed a lack of standardization of IPC protocols in their setting and felt that healthcare for women and pregnant people is not prioritized on a larger scale and within their hospitals.Conclusions:This study identified barriers to consistently implementing IPC practices in the labor and delivery setting. These barriers should be addressed through targeted interventions and the development of obstetric-specific IPC resources.

Nanopore-based sensing platforms have transformed single-molecule detection and analysis. The foundation of nanopore translocation experiments lies in conductance measurements, yet existing models, which are largely phenomenological, are inaccurate in critical experimental conditions such as thin and tightly fitting pores. Of the two components of the conductance blockade, channel and access resistance, the access resistance is poorly modeled. We present a comprehensive investigation of the access resistance and associated conductance blockade in thin nanopore membranes. By combining a first-principles approach, multiscale modeling, and experimental validation, we propose a unified theoretical modeling framework. The analytical model derived as a result surpasses current approaches across a broad parameter range. Beyond advancing our theoretical understanding, our framework’s versatility enables analyte size inference and predictive insights into conductance blockade behavior. Our results will facilitate the design and optimization of nanopore devices for diverse applications, including nanopore base calling and data storage.

This work reports Fick diffusion coefficients D11and thermal diffusivities ain binary liquid mixtures containing cyclohexane, n-decane, n-heptane, toluene, isobutylbenzene, 1-methylnaphthalene, methanol, ethanol, or acetone. The mixtures are investigated by dynamic light scattering at temperatures T= 298, 348, and 423 K close to saturation conditions. Besides equimolar composition, toluene-based binary mixtures with methanol, ethanol, or cyclohexane are investigated at toluene mole fractions between 0.1 and 0.9. The average relative expanded experimental uncertainties (k= 2) for D11and aare 5.3 and 8.3%. For the studied systems, the influence of molecular characteristics on the diffusivities as a function of Tand composition is discussed. While D11clearly depends on the molecular structure of the mixture components, i.e., alkane chain length, aliphatic or aromatic rings, or hydroxyl and carbonyl functional groups, such relationships were not resolvable for awithin the experimental uncertainties. For mixtures containing the polar species methanol, ethanol, or acetone, an influence of hydrogen bonding on D11was found. In general, the identified structure–property relationships agree with those reported in the literature for similar systems. Furthermore, a comparison of the present D11and adata with corresponding literature data is performed.

Mitral annular calcification is a chronic process involving degeneration and calcium deposition within the fibrous skeleton of the mitral valve annulus, which can lead to mitral valve dysfunction. It can be asymptomatic, or it can have pathologic sequelae leading to cardiovascular morbidity and mortality. Mitral annular calcification is increasingly recognized with the advancement of diagnostic imaging modalities, especially in an era with a growing elderly population. Its presence poses considerable challenges in terms of surgical and transcatheter management. Multiple surgical and transcatheter techniques have been developed to overcome these challenges. New transcatheter technologies are under investigation to tackle this problem.

We report the design and development of a transition-metal-free cross-coupling reaction of phenols and primary amines using a simple and readily available multifunctional reagent. The reactions work by induced proximity and electronic activation of both the nucleophile and the electrophile for net dehydrative C–N coupling reactions. Notably, the reactions do not involve the use of a transition metal for C–N bond formation, preactivation of the phenol electrophile, or exclusion of air or moisture. The mild conditions tolerate a broad range of functional groups and allow for this to be applied to the late-stage functionalization of complex substrates with a wide scope of coupling partners.

AIIRAseeks to transform agriculture by creating a new AI‐driven framework for modeling plants at various agronomically relevant scales. We accomplish this by designing and deploying AI‐driven predictive models that fuse diverse data with siloed domain knowledge. AIIRA's vision, illustrated in Figure 1, consists of four technical thrusts with cross‐cutting education, training, and outreach activities. Our activities are focused on theory, algorithms, and tools for the principled creation of goal‐oriented AI tools deployed at plant and field scales. Our use‐inspired AI developments are tightly integrated with USDA‐relevant challenges in crop improvement and sustainable crop production. Our strong social science focus ensures sustained AI adoption across the ag value chain. Our cyberinfrastructure (CI) efforts ensure cohesive, sustainable, and extensible CI to reproducibly share and manage data assets and analysis workflows to a diverse spectrum of the Ag community. Taken together, this will ensure long‐term payoffs in AI and agriculture. AIIRAhas established a new field of Cyber Agricultural Systemsat the intersection of plant science, agronomics, and AI. Our signature activities build the workforce for this new field through formal and informal educational activities. Through these activities, AIIRAcreates accessible pathways for underrepresented groups, especially Native Americans and women.

Many children with autism spectrum disorder (ASD) and other developmental disabilities (DD) transitioned to telehealth services due to the COVID-19 pandemic. Our objectives were to describe reductions in allied and behavioral healthcare services and receipt of caregiver training to deliver services at home because of COVID-19 for children with ASD and other DD, and factors associated with worse response to remote delivery of services for children with ASD.

Cirrhosis represents the end stage of chronic liver disease. Sub-Saharan Africa, a resource-constrained region, has a high burden of chronic liver disease, with causes including chronic viral hepatitis, excessive alcohol use, and metabolic dysfunction-associated steatotic liver disease (MASLD), the risk of which is burgeoning. The development of liver cirrhosis predicts for morbidity and mortality, driven by both liver dysfunction and the consequences of portal hypertension. Compensated cirrhosis portends a better prognosis than decompensated cirrhosis, highlighting the need for the early diagnosis of cirrhosis and its causes. With resource challenges, the diagnosis and management of cirrhosis is demanding, but less costly and less invasive interventions with substantial benefits, ranging from simple blood tests to transient elastography, are feasible in such settings. Simple interventions are also available to manage the complex manifestations of decompensation, such as β blockers in variceal bleeding prophylaxis, salt restriction and appropriate diuretic use in ascites, and lactulose and generic rifaximin in hepatic encephalopathy. Ultimately, managing the underlying causative factors of liver disease is key in improving prognosis. Management demands expanded policy interventions to increase screening and treatment for hepatitis B and C and reduce alcohol use and the metabolic factors driving MASLD. Furthermore, the skills needed for more specialised interventions, such as transjugular intrahepatic portosystemic shunt procedures and even liver transplantation, warrant planning, increased capacity, and support for regional centres of excellence. Such centres are already being developed in sub-Saharan Africa, demonstrating what can be achieved with dedicated initiatives and individuals.

Diamond, as the densest allotrope of carbon, displays a range of exemplary material properties that are attractive from a device perspective. Despite diamond displaying high carbon–carbon bond strength, ultrashort (femtosecond) pulse laser radiation can provide sufficient energy for highly localized internal breakdown of the diamond lattice. The less-dense carbon structures generated on lattice breakdown are subject to significant pressure from the surrounding diamond matrix, leading to highly unusual formation conditions. By tailoring the laser dose delivered to the diamond, it is shown that it is possible to create continuously modified internal tracks with varying electrical conduction properties. In addition to the widely reported conducting tracks, conditions leading to semiconducting and insulating written tracks have been identified. High-resolution transmission electron microscopy (HRTEM) is used to visualize the structural transformations taking place and provide insight into the different conduction regimes. The HRTEM reveals a highly diverse range of nanocarbon structures are generated by the laser irradiation, including many signatures for different so-called diaphite complexes, which have been seen in meteorite samples and seem to mediate the laser-induced breakdown of the diamond. This work offers insight into possible formation methods for the diamond and related nanocarbon phases found in meteorites.

Bronchiolitis and asthma have similar acute clinical presentations in young children yet have opposing treatment recommendations. We aimed to assess the role of age and other factors in the diagnosis of bronchiolitis and asthma in children <24 months of age.We conducted a retrospective cross-sectional analysis of the Pediatric Health Information System database. We included children aged <2 years diagnosed with bronchiolitis, asthma, wheeze, or bronchospasm in emergency department or hospital encounters from 2017 to 2021. We described variation by age and between institutions. We used mixed-effects models to assess factors associated with a non-bronchiolitis diagnosis in children 12 to 23 months of age.We included 554 158 encounters from 42 hospitals. Bronchiolitis made up 98% of encounters for children <3 months of age, whereas asthma diagnoses increased with age and were included in 44% of encounters at 23 months of age. Diagnosis patterns varied widely between hospitals. In children 12 to 23 months of age, the odds of a non-bronchiolitis diagnosis increased with month of age (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.12–1.13), male sex (OR 1.37, 95% CI 1.35–1.40), non-Hispanic Black race (OR 1.54, 95% CI 1.50–1.58), number of previous encounters (OR 2.73, 95% CI 2.61–2.86, for 3 or more encounters), and previous albuterol use (OR 2.24, 95% CI 2.16–2.32).Non-bronchiolitis diagnoses and the use of inhaled bronchodilators and systemic steroids for acute wheezing respiratory illness increase with month of age in children aged 0 to 23 months. Better definitions of clinical phenotypes of bronchiolitis and asthma would allow for more appropriate treatment in acute care settings, particularly in children 12 to 23 months of age.

BackgroundPatients with decompensated cirrhosis experience high mortality rates. Current prognostic scores, including the model for end-stage liver disease (MELD), may underperform in settings other than in those they were initially developed. Novel biomarkers have been proposed to improve prognostication accuracy and even to predict development of complications.MethodsWe performed a systematic review and meta-analysis on novel urine and blood biomarkers and their ability to predict 90-day mortality in patients with decompensated cirrhosis. Secondary outcomes included 28-day and 1-year mortality, and development of acute-on-chronic liver failure, acute kidney injury and other complications. To overcome differences in units, temporal changes in assays and reporting heterogeneity, we used the ratio of means (RoM) as measure of association for assessing strength in predicting outcomes. An RoM>1 implies that the mean biomarker level is higher in those that develop the outcome than in those that do not.ResultsOf 6629 unique references, 103 were included, reporting on 29 different biomarkers, with a total of 31 362 biomarker patients. Most studies were prospective cohorts of hospitalised patients (median Child-Pugh-Turcotte score of 9 and MELD score of 18). The pooled 90-day mortality rate was 0.27 (95% CI 0.24 to 0.29). The RoM for predicting 90-day mortality was highest for interleukin 6 (IL-6) (2.56, 95% CI 2.39 to 2.74), followed by urinary neutrophil gelatinase-associated lipocalin (uNGAL) (2.42, 95% CI 2.20 to 2.66) and copeptin (2.33, 95% CI 2.17 to 2.50). These RoMs were all higher than for MELD (1.44, 95% CI 1.42 to 1.46).ConclusionNovel biomarkers, including IL-6, uNGAL and copeptin, can probably improve prognostication of patients with decompensated cirrhosis compared with MELD alone.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1–4, but the efficacy of CAR T cell therapy in solid tumours has been limited5. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more ‘stem-like’ phenotype and increased mitochondrial mass6–8. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.

This article has supplementary material on the web site: www.jdbp.org.