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Abstract Nature uses fibrous structures for sensing and structural functions as observed in hairs, whiskers, stereocilia, spider silks, and hagfish slime thread skeins. Here, we demonstrate multi-nozzle printing of 3D hair arrays having freeform trajectories at a very high rate, with fiber diameters as fine as 1.5 µm, continuous lengths reaching tens of centimeters, and a wide range of materials with elastic moduli from 5 MPa to 3500 MPa. This is achieved via 3D printing by rapid solvent exchange in high yield stress micro granular gel, leading to radial solidification of the extruded polymer filament at a rate of 2.33 μm/s. This process extrudes filaments at 5 mm/s, which is 500,000 times faster than meniscus printing owing to the rapid solidification which prevents capillarity-induced fiber breakage. This study demonstrates the potential of 3D printing by rapid solvent exchange as a fast and scalable process for replicating natural fibrous structures for use in biomimetic functions.

Abstract Pediatric neurological injury and disease is a critical public health issue due to increasing rates of survival from primary injuries (e.g., cardiac arrest, traumatic brain injury) and a lack of monitoring technologies and therapeutics for treatment of secondary neurological injury. Translational, preclinical research facilitates the development of solutions to address this growing issue but is hindered by a lack of available data frameworks and standards for the management, processing, and analysis of multimodal datasets. Here, we present a generalizable data framework that was implemented for large animal research at the Children’s Hospital of Philadelphia to address this technological gap. The presented framework culminates in a custom, interactive dashboard for exploratory analysis and filtered dataset download. Compared with existing clinical and preclinical data management solutions, the presented framework better enables management of various data types (single measure, repeated measures, time series, and imaging), integration of datasets for comparison across experimental models, cohorts, and groups, and facilitation of predictive modeling from integrated datasets. Further, a predictive model development use case demonstrated utilization and value of the data framework. The general outline of a preclinical data framework presented here can serve as a template for other translational research labs that generate heterogeneous datasets and require a dynamic platform that can easily evolve alongside their research.

Abstract Key message We provide data on seedlot germination potential—a key trait related to regeneration—of 12 oak species. Germination was tested at the University of Granada following international protocols with 8985 acorns from 93 batches and 16 countries across Europe. Data on germination probability, acorn origin, mass, and moisture content measured on another 4544 acorns are available at https://doi.org/10.30827/Digibug.87318 . Associated metadata are available at https://metadata-afs.nancy.inra.fr/geonetwork/srv/fre/catalog.search#/metadata/a742c6d8-bc37-4ca2-8b81-2447c5a8858d .

Abstract Inhibiting glycogen synthase kinase 3 (GSK3) improves muscle function, metabolism, and bone health in many diseases and conditions; however, whether GSK3 should be targeted for Duchenne muscular dystrophy (DMD), a severe muscle wasting disorder with no cure, remains unknown. Here, we show the effects of GSK3 inhibition in male DBA/2J (D2) and C57BL/10 (C57) mdx mice. Treating D2 mdx mice with GSK3 inhibitors alone or in combination with aerobic exercise improves muscle strength, endurance, and morphology, attenuates the hypermetabolic phenotype, and enhances insulin sensitivity. GSK3 inhibition in C57 mdx mice also improves muscle fatigue resistance and increases cage ambulation. Moreover, muscle-specific GSK3 knockdown in mdx mice augments muscle force production and endurance. In both mdx strains, GSK3 inhibition increases bone mineral content and density. Overall, these improvements to muscle, metabolic, and bone health with GSK3 inhibition in mdx mice may have clinical implications for patients with DMD, where the current standard of care, glucocorticoids, delay the loss of ambulation but increase the risk for insulin resistance and osteoporosis. Along with our observation of lowered β-catenin content in DMD myoblasts, a known cellular target for GSK3, this study provides ample evidence in support of inhibiting GSK3 for this disease.

Bow Hunter's syndrome (BHS) is an uncommon condition characterized by impingement of one of the two vertebral arteries induced by cervical rotation, causing symptomatic vertebrobasilar insufficiency of the posterior cerebral circulation. We report a case of BHS in an 84-year-old male. Two months following a motor vehicle accident, the patient presented to an urgent care facility with subsequent transfer to the emergency department with complaints of lightheadedness upon right-lateral head movement. A cerebral angiogram demonstrated mild focal stenosis in the dominant left vertebral artery at the C2 level when in neutral position with significant worsening of the stenosis in the right-lateral head position with absent anterograde flow, consistent with BHS. Resultantly, the patient was referred for neurosurgery and successfully underwent placement of right-sided C2-C4 postero-lateral instrumentation and left-sided C2-C3 laminar screws projected towards the right side. This case highlights the importance of imaging in BHS diagnosis and guidance for treatment, as well as the need for a surgical standard of care for BHS patients.

Importance: Patients with underlying cardiac disease form a considerable proportion of pediatric patients who experience in-hospital cardiac arrest. In pediatric patients after cardiac surgery, CPR with abdominal compressions alone (AC-CPR) may provide an alternative to standard chest compression CPR (S-CPR) with additional procedural and physiologic advantages. Objective: Quantitatively describe hemodynamics during cardiopulmonary resuscitation (CPR) and outcomes of infants who received only abdominal compressions (AC-CPR). Design: This is a sub-group analysis of the prospective, observational cohort from the ICU-RESUS trial NCT028374497. Setting & Patients: A single site quaternary care pediatric cardiothoracic intensive care unit enrolled in the ICU-RESUS trial. Patients less than 1 year of age with congenital heart disease who required compressions during cardiac arrest. Interventions: Use of AC-CPR during cardiac arrest resuscitation. Measurements and Main Results: Invasive arterial line waveforms during CPR were analyzed for 11 patients (10 surgical cardiac and 1 medical cardiac). Median weight was 3.3 kg [IQR 3.0, 4.0]; and median duration of CPR was 5.0 [3.0, 20.0] minutes. Systolic (median 57 [IQR 48, 65] mmHg) and diastolic (median 32 [IQR 24, 43] mmHg) blood pressures were achieved with a median rate of 114 [IQR 100, 124] compressions per minute. Return of spontaneous circulation was obtained in 9 of 11 (82%) patients; 2 patients (18%) were cannulated for extracorporeal cardiopulmonary resuscitation (ECPR) and 6 (55%) survived to hospital discharge with favorable neurologic outcome. Conclusions: AC-CPR may offer an alternative method to maintain perfusion for infants who experience cardiac arrest. This may have particular benefit in pediatric patients after cardiac surgery for whom external chest compressions may be harmful due to anatomic and physiologic considerations.

Peripheral nerve injuries are potentially devastating injuries leading to pain and impairment in motor and sensory functions. Since the first published use of microsurgical epineural repair of peripheral nerves in 1964, a wide variety of adjuncts have been studied. Polyethylene glycol is a fusogen that has been shown to restore axolemmal membranes. The use of polyethylene glycol in nerve injuries was first described in 1986, and animal studies have shown fusion of transected sensory and motor nerves following early application at the time of surgical repair with improved motor and sensory outcomes. Early human clinical trials have shown promising results, although more data are needed to provide specific indications and protocols. This article summarizes the background, current evidence, and future directions as well as potential applications of polyethylene glycol–mediated nerve fusion.

Background: Since various social determinants of health (SDOH) have the potential to impact the utilization and postoperative outcomes of rotator cuff repair (RCR), a review of the literature is warranted. Therefore, the purpose of this systematic review was to evaluate the effects of SDOH on RCR utilization and postoperative outcomes in order to recognize external factors that may influence patients’ access to RCR and optimal clinical outcomes. Methods: Search terms related to RCR, utilization, outcomes, and SDOH were used to identify studies that reported associations between any SDOH (as defined by the World Health Organization) and RCR utilization, access, cost, or postoperative outcomes. Articles that did not isolate RCR or did not evaluate an SDOH were excluded. Nonrandomized studies were evaluated for study quality using the Methodological Index for Nonrandomized Studies score. Due to the heterogeneity of the reported data, only qualitative analysis was possible. Results: Overall, 842 articles were considered for inclusion and 14 studies were included in qualitative analysis. The average Methodological Index for Nonrandomized Studies score of included studies was 14.1 ± 5.0. The SDOH most frequently evaluated were insurance status and race/ethnicity. Non-White race is associated with lower odds of surgery and physical therapy (PT) utilization, as well as delayed treatment. Similarly, public insurance is associated with lower PT and surgery utilization rates and decreased acceptance for postoperative PT. Postoperatively, public insurance is associated with worse patient-reported outcome scores and lower return to work rates. Conclusion: Various SDOH can influence access, utilization, and outcomes of RCR. Orthopedic surgeons should be aware of how factors of race and insurance type can influence a patient’s treatment and recovery after RCR.

Abstract Identifying sensitive and specific measures that can quantify myelin are instrumental in characterizing microstructural changes in neurological conditions. Neuroimaging transcriptomics is emerging as a valuable technique in this regard, offering insights into the molecular basis of promising candidates for myelin quantification, such as myelin water fraction (MWF). We aimed to demonstrate the utility of neuroimaging transcriptomics by validating MWF as a myelin measure. We utilized data from a normative MWF brain atlas, comprised of 50 healthy subjects (mean age = 25 years, range = 17–42 years) scanned at 3 Tesla. Magnetic resonance imaging data included myelin water imaging to extract MWF and T1 anatomical scans for image registration and segmentation. We investigated the inter-regional distributions of gene expression data from the Allen Human Brain Atlas in conjunction with inter-regional MWF distribution patterns. Pearson correlations were used to identify genes with expression profiles mirroring MWF. The Single Cell Type Atlas from the Human Protein Atlas was leveraged to classify genes into gene sets with high cell type specificity, and a control gene set with low cell type specificity. Then, we compared the Pearson correlation coefficients for each gene set to determine if cell type-specific gene expression signatures correlate with MWF. Pearson correlation coefficients between MWF and gene expression for oligodendrocytes and adipocytes were significantly higher than for the control gene set, whereas correlations between MWF and inhibitory/excitatory neurons were significantly lower. Our approach in integrating transcriptomics with neuroimaging measures supports an emerging technique for understanding and validating MRI-derived markers such as MWF.

Abstract Neurological and cardiac injuries are significant contributors to morbidity and mortality following pediatric in-hospital cardiac arrest (IHCA). Preservation of mitochondrial function may be critical for reducing these injuries. Dimethyl fumarate (DMF) has shown potential to enhance mitochondrial content and reduce oxidative damage. To investigate the efficacy of DMF in mitigating mitochondrial injury in a pediatric porcine model of IHCA, toddler-aged piglets were subjected to asphyxia-induced CA, followed by ventricular fibrillation, high-quality cardiopulmonary resuscitation, and random assignment to receive either DMF (30 mg/kg) or placebo for four days. Sham animals underwent similar anesthesia protocols without CA. After four days, tissues were analyzed for mitochondrial markers. In the brain, untreated CA animals exhibited a reduced expression of proteins of the oxidative phosphorylation system (CI, CIV, CV) and decreased mitochondrial respiration (p

The mesolimbic pathway connects ventral tegmental area dopaminergic neurons and striatal medium spiny neurons, playing a critical role in reward and stress behaviors. Exposure to substances of abuse during development and adulthood has been linked to adverse outcomes and molecular changes. The rise of human cell repositories and whole-genome sequences enables human functional genomics ‘in a dish’, offering insights into human-specific responses to substances of abuse. Continued development of new models is needed, and the characterization of in vitro models is also necessary to ensure appropriate experimental designs and the accurate interpretation of results. This study introduces new culture conditions for generating medium spiny neurons and dopaminergic neurons with an early common media, allowing for coculture and assembloid generation. It then provides a comprehensive characterization of these and prior models and their responses to substances of abuse. Single-cell analysis reveals cell-type-specific transcriptomic responses to dopamine, cocaine, and morphine, including compound and cell-type-specific transcriptomic signatures related to neuroinflammation and alterations in signaling pathways. These findings offer a resource for future genomics studies leveraging human stem cell-derived models.

To answer NASA’s call for a sensitive X-ray observatory in the 2030s, we present the High Energy X-ray Probe (HEX-P) mission concept. HEX-P is designed to provide the required capabilities to explore current scientific questions and make new discoveries with a broadband X-ray observatory that simultaneously measures sources from 0.2 to 80 keV. HEX-P’s main scientific goals include: 1) understand the growth of supermassive black holes and how they drive galaxy evolution; 2) explore the lower mass populations of white dwarfs, neutron stars, and stellar-mass black holes in the nearby universe; 3) explain the physics of the mysterious corona, the luminous plasma close to the central engine of accreting compact objects that dominates cosmic X-ray emission; and 4) find the sources of the highest energy particles in the Galaxy. These goals motivate a sensitive, broadband X-ray observatory with imaging, spectroscopic, and timing capabilities, ensuring a versatile platform to serve a broad General Observer (GO) and Guest Investigator (GI) community. In this paper, we present an overview of these mission goals, which have been extensively discussed in a collection of more than a dozen papers that are part of this Research Topic volume. The proposed investigations will address key questions in all three science themes highlighted by Astro2020, including their associated priority areas. HEX-P will extend the capabilities of the most sensitive low- and high-energy X-ray satellites currently in orbit and will complement existing and planned high-energy, time-domain, and multi-messenger facilities in the next decade.

IntroductionCentral line-associated bloodstream infections (CLABSI) are prevalent and preventable hospital-acquired infections associated with high morbidity and costs. Disparities based on race, ethnicity, and hospital factors remain underexplored. This study compares cost, length of stay, and mortality for adults with CLABSI by race-ethnicity, hospital location-teaching status, and geographic region in the United States using data from the National Inpatient Sample (NIS) database from 2016 to 2020.MethodsThe hospitalization cohort included adults diagnosed with CLABSI, excluding those with primary CLABSI diagnoses, cancer, immunosuppressed states, or neonatal conditions. Primary outcomes were in-hospital mortality, length of stay, and hospital costs, adjusted to mid-year 2020 US dollars. Independent variables included race-ethnicity, hospital location-teaching status, and geographic region. All analyses accounted for NIS sampling design.ResultsFrom 2016 to 2020, there were approximately 19,835 CLABSI hospitalizations. The overall in-hospital mortality rate was 9.1%, with a median hospital stay of 16.9 days and median cost of $44,810. Hispanic patients experienced significantly higher mortality, longer length of stay, and higher costs compared to non-Hispanic Black and White patients. Urban teaching hospitals had longer stays and higher costs than rural and urban non-teaching hospitals. Regionally, the Northeast and West had higher costs and longer stays than the Midwest and South, but mortality rates did not differ significantly.ConclusionThis study highlights significant disparities in CLABSI outcomes based on demographic factors. Addressing these disparities is crucial for improving CLABSI management and healthcare equity. Further research should explore the underlying causes of these differences to inform targeted interventions.

Mean daily temperature effects on plant development rates and quality were evaluated for compact container-grown tomato (Solanum lycopersicum). Compact tomato varieties ‘Siam’ and ‘Red Velvet’ were grown in greenhouses at 18 to 26 °C (Expt. 1) and 20 to 30 °C (Expt. 2) under supplemental high-pressure sodium lighting and 16-h photoperiod. The number of days to first open flower, first ripe fruit and from flower to ripe fruit were measured and development rates calculated by taking the reciprocal (e.g., 1/d). Temperature effects were predicted by fitting a linear (for first open flower) and a nonlinear exponential function (for first ripe fruit and between first open flower and ripe fruit), which included base temperature (Tmin) and maximum developmental rate (Rmax, 1/d) parameters. Plant quality attributes were measured in Expt. 2. As temperature increased, the time to flower and fruit decreased (i.e., developmental rates increased) for both varieties. Estimated Tmin was 8.7 °C for ‘Siam’ and 11.4 °C for ‘Red Velvet’, whereas Rmax was similar between cultivars (0.030 at fruit and 0.037 from flower to fruit). ‘Siam’ and ‘Red Velvet’ grown at ≈25 °C had a relatively short crop time, compact canopy, adequate fruit size, and a high number of fruits per plant at finish. Compact tomatoes are new crops being grown by greenhouse floriculture operations for ornamental and edible value, and the information from this study can help growers schedule these crops to meet critical market windows and determine the impacts of changing growing temperature on crop timing and quality.

Introduction: Swine exhibit cerebral cortex mitochondrial dysfunction and neuropathologic injury after hypoxic cardiac arrest treated with hemodynamic-directed CPR (HD-CPR) despite normal Cerebral Performance Category scores. We analyzed the temporal evolution of plasma protein biomarkers of brain injury and inflammatory cytokines, as well as cerebral cortical mitochondrial injury and neuropathology for five days following pediatric asphyxia-associated cardiac arrest treated with HD-CPR. Methods: One-month-old swine underwent asphyxia associated cardiac arrest, 10–20 min of HD-CPR (goal SBP 90 mmHg, coronary perfusion pressure 20 mmHg), and randomization to post-ROSC survival duration (24, 48, 72, 96, 120 h; n = 3 per group) with standardized post-resuscitation care. Plasma neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and cytokine levels were collected pre-injury and 1, 6, 24, 48, 72, 96, and 120 h post-ROSC. Cerebral cortical tissue was assessed for: mitochondrial respirometry, mass, and dynamic proteins; oxidative injury; and neuropathology. Results: Relative to pre-arrest baseline (9.4 pg/ml [6.7–12.6]), plasma NfL was increased at all post-ROSC time points. Each sequential NfL measurement through 48 h was greater than the previous value {1 h (12.7 pg/ml [8.4–14.6], p = 0.01), 6 h (30.9 pg/ml [17.7–44.0], p = 0.0004), 24 h (59.4 pg/ml [50.8–96.1], p = 0.0003) and 48 h (85.7 pg/ml [61.9–118.7], p = 0.046)}. Plasma GFAP, inflammatory cytokines or cerebral cortical tissue measurements were not demonstrably different between time points. Conclusions: In a swine model of pediatric cardiac arrest, plasma NfL had an upward trajectory until 48 h post-ROSC after which it remained elevated through five days, suggesting it may be a sensitive marker of neurologic injury following pediatric cardiac arrest.

Abstract Background In Alzheimer’s disease (AD), microglia surround extracellular plaques and mount a sustained inflammatory response, contributing to the pathogenesis of the disease. Identifying approaches to specifically target plaque-associated microglia (PAMs) without interfering in the homeostatic functions of non-plaque associated microglia would afford a powerful tool and potential therapeutic avenue. Methods Here, we demonstrated that a systemically administered nanomedicine, hydroxyl dendrimers (HDs), can cross the blood brain barrier and are preferentially taken up by PAMs in a mouse model of AD. As proof of principle, to demonstrate biological effects in PAM function, we treated the 5xFAD mouse model of amyloidosis for 4 weeks via systemic administration (ip, 2x weekly) of HDs conjugated to a colony stimulating factor-1 receptor (CSF1R) inhibitor (D-45113). Results Treatment resulted in significant reductions in amyloid-beta (Aβ) and a stark reduction in the number of microglia and microglia-plaque association in the subiculum and somatosensory cortex, as well as a downregulation in microglial, inflammatory, and synaptic gene expression compared to vehicle treated 5xFAD mice. Conclusions This study demonstrates that systemic administration of a dendranib may be utilized to target and modulate PAMs.

Abstract Background The duplex kidney is one of the common congenital anomalies of the kidney and urinary tract. We present two cases of renal tumor accompanied with ipsilateral duplex kidney. The image of the tumor, renal artery system and collecting system were rendered by AI software (Fujifilm’s Synapse® AI Platform) to support the diagnosis and surgical planning. Case presentation Two Vietnamese patients (a 45-year-old man and a 54-year-old woman) with incidental cT1 renal cell carcinoma (RCC) were confirmed to have ipsilateral duplex kidneys by 3D reconstruction AI technique. One patient had a Renal score 9ah tumor of left kidney while the other had a Renal score 9 × tumor of right kidney in which a preoperative CT scan failed to identify a diagnosis of duplex kidney. Using the Da Vinci platform, we successfully performed robotic partial nephrectomy without any damage to the collecting system in both cases. Conclusion RCC with duplex kidneys is a rare condition. By utilizing a novel AI reconstruction technique with adequate information, two patients with RCC in duplex kidneys were successfully performed robotic partial nephrectomy without complication.

Abstract Background Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) is the most abundant soluble protein in nature. Extensive studies have been conducted for improving its activity in photosynthesis through approaches like protein engineering. Concurrently, multiple biochemical and radiolabeling assays have been developed for determining its activity. Although these existing assays yield reliable results, they require addition of multiple external components, rendering them less convenient and expensive. Therefore, in this study, we have developed two relatively cheaper, convenient, and easily reproducible assays for quantitative and qualitative estimation of RuBisCO activity. Results We simplified a contemporary NADH based spectrophotometric RuBisCO assay by using cyanobacterial cell lysate as the source for Calvin cycle enzymes. We analyzed the influence of inorganic carbon substrates, CO2 and NaHCO3, and varying protein concentrations on RuBisCO activity. Ribulose-1,5-bisphosphate (RuBP) consumption rates for the cultures grown under 5% CO2 were 5–7 times higher than the ones grown with 20 mM NaHCO3, at different protein concentrations. The difference could be due to the impaired activity of carbonic anhydrase in the cell lysate, which is required for the conversion of HCO3 − to CO2. The highest RuBisCO activity of 2.13 nmol of NAD+/ µg of Chl-a/ min was observed with 50 µg of protein and 5% CO2. Additionally, we developed a novel RNA-sensor based fluorescence assay that is based on the principle of tracking the kinetics of ATP hydrolysis to ADP during the conversion of 3-phosphoglycerate (3-PG) to 1,3-bisphosphoglycerate (1,3-BPG) in the Calvin cycle. Under in vitro conditions, the fluorometric assay exhibited ~ 3.4-fold slower reaction rate (0.37 min−1) than the biochemical assay when using 5% CO2. We also confirmed the in vivo application of this assay, where increase in the fluorescence was observed with the recombinant strain of Synechocystis sp. PCC 6803 (SSL142) expressing the ADP-specific RNA sensor, compared to the WT. In addition, SSL142 exhibited three-fold higher fluorescence when supplemented with 20 mM NaHCO3 as compared to the cells that were grown without NaHCO3 supplementation. Conclusions Overall, we have developed a simplified biochemical assay for monitoring RuBisCO activity and demonstrated that it can provide reliable results as compared to the prior literature. Furthermore, the biochemical assay using 5% CO2 (100% relative activity) provided faster RuBP consumption rate compared to the biochemical assay utilizing 20 mM NaHCO3 (30.70% relative activity) and the in vitro fluorometric assay using 5% CO2 (29.64% relative activity). Therefore, the absorbance-based biochemical assay using 5% CO2 or higher would be suitable for in vitro quantification of the RuBisCO activity. On the other hand, the RNA-sensor based in vivo fluorometric assay can be applied for qualitative analysis and be used for high-throughput screening of RuBisCO variants. As RuBisCO is an enzyme shared amongst all the photoautotrophs, the assays developed in this study can easily be extended for analyzing the RuBisCO activities even in microalgae and higher plants.

Using methods of DFT, we investigated the effect of electron withdrawing and electron donating groups on the relative stability of tentative glycosyl donor reaction intermediates. The calculation shows that by changing the stereoelectronic properties of the protecting group, we can influence the stability of the dioxolenium type of intermediates by up to 10 kcal mol−1, and that by increasing nucleophillicity of the 4-O-Bz group, the dioxolenium intermediate becomes more stable than a triflate–donor pair. We exploited this mechanism to design galactosyl donors with custom protecting groups on O2 and O4, and investigated the outcome of the reaction with cyclohexanol. The reaction showed no change in the product distribution, which suggests that the neighboring group participation takes precedence over remote group participation due to kinetic barriers.

The mean daily temperature effects on plant development rates and quality of compact container-grown pepper were evaluated. Compact pepper cultivars Fresh Bites Yellow and Hot Burrito were grown in greenhouses at 18 to 26 °C (Expt. 1) and 20 to 30 °C (Expt. 2) under supplemental high-pressure sodium lighting and a 16-hour photoperiod. The number of days to first open flower, to first ripe fruit, and from flower to ripe fruit were measured and the development rates calculated by taking the reciprocal (e.g., 1/day). Temperature effects were predicted by fitting a nonlinear exponential function that included the base temperature (Tmin) and maximum developmental rate (Rmax) parameters. Plant quality attributes were measured during Expt. 2. As the temperature increased, the times to flower and fruit decreased (i.e., developmental rates increased) for both cultivars. The estimated Tmin was 13.3 °C for ‘Fresh Bites Yellow’, and that for ‘Hot Burrito’ was 9.3 °C, whereas the Rmax was similar between cultivars (averages of 0.0488 at flower, 0.0190 at fruit, and 0.0252 from flower to fruit). ‘Fresh Bites Yellow’ and ‘Hot Burrito’ grown at ≈25 °C had a relatively short crop time, compact canopy, large fruit size, and high number of fruits per plant at finish. Compact peppers are new crops being grown by greenhouse floriculture operations for their ornamental and edible value, and the information from this study can help growers schedule these crops to meet critical market windows and determine the impacts of changing the growing temperature on crop timing and quality.

Introduction: While randomized controlled trials remain the reference standard for evaluating treatment efficacy, there is an increased interest in the use of external control arms (ECA), namely in oncology, using real-world data (RWD). Challenges related to measurement of real-world oncology endpoints, like progression-free survival (PFS), are one factor limiting the use and acceptance of ECAs as comparators to trial populations. Differences in how and when disease assessments occur in the real-world may introduce measurement error and limit the comparability of real-world PFS (rwPFS) to trial progression-free survival. While measurement error is a known challenge when conducting an externally-controlled trial with real-world data, there is limited literature describing key contributing factors, particularly in the context of multiple myeloma (MM).Methods: We distinguish between biases attributed to how endpoints are derived or ascertained (misclassification bias) and when outcomes are observed or assessed (surveillance bias). We further describe how misclassification of progression events (i.e., false positives, false negatives) and irregular assessment frequencies in multiple myeloma RWD can contribute to these biases, respectively. We conduct a simulation study to illustrate how these biases may behave, both individually and together.Results: We observe in simulation that certain types of measurement error may have more substantial impacts on comparability between mismeasured median PFS (mPFS) and true mPFS than others. For instance, when the observed progression events are misclassified as either false positives or false negatives, mismeasured mPFS may be biased towards earlier (mPFS bias = −6.4 months) or later times (mPFS bias = 13 months), respectively. However, when events are correctly classified but assessment frequencies are irregular, mismeasured mPFS is more similar to the true mPFS (mPFS bias = 0.67 months).Discussion: When misclassified progression events and irregular assessment times occur simultaneously, they may generate bias that is greater than the sum of their parts. Improved understanding of endpoint measurement error and how resulting biases manifest in RWD is important to the robust construction of ECAs in oncology and beyond. Simulations that quantify the impact of measurement error can help when planning for ECA studies and can contextualize results in the presence of endpoint measurement differences.

Fungemia is common in critically ill patient populations, and is associated with a high rate of mortality, especially when caused by nonalbicans Candida species. Herein, we describe a fatal case of fungemia following cardiothoracic surgery in which the organism, initially identified as Candida inconspicua, represents a novel species: Pichia alaskaensis.

Introduction: Physiology-guided cardiopulmonary resuscitation (CPR) offers the potential to optimize resuscitation and enable early prognosis. Methods: Physiology-Guided CPR was one of six focus topic for the Wolf Creek XVII Conference held on June 14–17, 2023 in Ann Arbor, Michigan, USA. International thought leaders and scientists in the field of cardiac arrest resuscitation from academia and industry were invited. Participants submitted via online survey knowledge gaps, barriers to translation and research priorities for each focus topic. Expert panels used the survey results and their own perspectives and insights to create and present a preliminary unranked list for each category, which was then debated, revised and ranked by all attendees to identify the top 5 for each category. Results: Top knowledge gaps include identifying optimal strategies for the evaluation of physiology-guided CPR and the optimal values for existing patients using patient outcomes. The main barriers to translation are the limited usability outside of critical care environments and the training and equipment required for monitoring. The top research priorities are the development of clinically feasible and reliable methods to continuously and non-invasively monitor physiology during CPR and prospective human studies proving targeting parameters during CPR improves outcomes. Conclusion: Physiology-guided CPR has the potential to provide individualized resuscitation and move away from a one-size-fits-all approach. Current understanding is limited, and clinical trials are lacking. Future developments need to consider the clinical application and applicability of measurement to all healthcare settings. Therefore, clinical trials using physiology-guided CPR for individualisation of resuscitation efforts are needed.

Introduction: Carbon fiber with reinforced polyetheretherketone (CFR-PEEK) implants have been utilized and researched in orthopedic trauma; however, CFR-PEEK implants may also have potential in orthopedic oncology. Therefore, the purpose of this case series was to report post-operative outcomes and radiographic healing of two patients who received CFR-PEEK plating and nailing for intercalary tumor resection with tibial allograft. Methodology: Two patients who underwent CFR-PEEK plating and nailing for intercalary resection with tibial allograft reconstruction were identified. Post-operative encounters were evaluated for any complications, reoperations, and progress of radiographic healing. Results: The first patient was diagnosis with adamantinoma and ultimately had a complication-free recovery throughout 2.5-year follow-up. The second patient presented with a recurrent proximal tibia osteosarcoma after tibial curettage 14 years prior, and has had a complication-free recovery throughout 1-year follow-up. The radiographic time to union was determined to be six months for both patients and was confirmed with clinical examination. Conclusion: Both patients who received CFR-PEEK plating and nailing for intercalary resection with tibial allograft had a successful surgical recovery with no post-operative complications. CFR-PEEK implants may be safe and effective for intercalary resection with tibial allograft, however future larger comparative studies are needed. Level of evidence: IV.

Coccidioidomycosis, also known as San Joaquin Valley fever, is an illness caused by the dimorphic fungus Coccidioides. Coccidioidomycosis is endemic to desert regions of the Western Hemisphere, including California, Arizona, Utah, Nevada, and New Mexico. We report a case of disseminated coccidioidomycosis in a 42-year-old male. Months after an upper respiratory infection of unidentified origin, the patient began experiencing back pain. The persistence of the back pain prompted MRI and CT imaging, which revealed lytic lesions. His clinical and radiological presentation mimicked, and was originally approached, as if it were a malignancy. Metastasis or multiple myeloma were considered the most likely differential diagnoses. As a result, the patient underwent surgical exploration. Pathology results indicated the presence of a fungal infection, without evidence of malignancy. PCR confirmed the diagnosis of coccidioidomycosis. The patient began treatment with fluconazole 800 mg daily and is anticipated to receive antifungal treatment for an indefinite period.

Abstract Successes in biocatalytic polyester recycling have raised the possibility of deconstructing alternative polymers enzymatically, with polyamide (PA) being a logical target due to the array of amide-cleaving enzymes present in nature. Here, we screen 40 potential natural and engineered nylon-hydrolyzing enzymes (nylonases), using mass spectrometry to quantify eight compounds resulting from enzymatic nylon-6 (PA6) hydrolysis. Comparative time-course reactions incubated at 40-70 °C showcase enzyme-dependent variations in product distributions and extent of PA6 film depolymerization, with significant nylon deconstruction activity appearing rare. The most active nylonase, a NylCK variant we rationally thermostabilized (an N-terminal nucleophile (Ntn) hydrolase, NylCK-TS, T m = 87.4 °C, 16.4 °C higher than the wild-type), hydrolyzes 0.67 wt% of a PA6 film. Reactions fail to restart after fresh enzyme addition, indicating that substrate-based limitations, such as restricted enzyme access to hydrolysable bonds, prohibit more extensive deconstruction. Overall, this study expands our understanding of nylonase activity distribution, indicates that Ntn hydrolases may have the greatest potential for further development, and identifies key targets for progressing PA6 enzymatic depolymerization, including improving enzyme activity, product selectivity, and enhancing polymer accessibility.

The next generation of infrared (IR) sensors may enable unprecedented applications in fields like spectroscopy, health monitoring, and communication systems. For instance, metasurface-enhanced micro-electromechanical system (MEMS)-based IR sensors have demonstrated excellent performance in terms of responsivity and spectral-selectivity. However, it is burdensome to experimentally determine the performance limits of this and other IR sensing technologies as it requires time-consuming and expensive systematic testing not always feasible in research settings. To address this challenge, an automated solution for characterizing miniaturized sensing devices is presented in this paper and applied to experimentally determine the performance limits of MEMS-based IR sensors. The system offers low-cost, rapid, and automated characterization of on-chip IR sensors, determining key performance metrics such as noise, responsivity, and noise-equivalent power. The platform is flexible, easily adapted to different types of devices, chip layouts, and light sources, and is designed to test a large number of sensors within the same wafer −spending ~20 seconds per device− using a combination of optical and radiofrequency interrogation techniques. The system has been applied to test over 1500 MEMS-based IR sensors. Collected data revealed hidden trade-offs between responsivity and noise with respect to the device thickness and allowed a statistical analysis of sensing response versus device geometrical dimensions. The best-performing devices exhibit a quality factor, responsivity, fluctuation induced noise, and noise-equivalent power of 2391, 164 Hz/nW, 0.257 Hz/ $\sqrt {\mathbf {Hz}}$ , and 5.01 pW/ $\sqrt {\mathbf {Hz}}$ respectively. The proposed automated platform provides an efficient and cost-effective solution for characterizing the next generation of IR sensing devices.

Abstract Antipsychotic (AP)-naive first-episode psychosis (FEP) patients display early dysglycemia, including insulin resistance and prediabetes. Metabolic dysregulation may therefore be intrinsic to psychosis spectrum disorders (PSDs), independent of the metabolic effects of APs. However, the potential biological pathways that overlap between PSDs and dysglycemic states remain to be identified. Using meta-analytic approaches of transcriptomic datasets, we investigated whether AP-naive FEP patients share overlapping gene expression signatures with non-psychiatrically ill early dysglycemia individuals. We meta-analyzed peripheral transcriptomic datasets of AP-naive FEP patients and non-psychiatrically ill early dysglycemia subjects to identify common gene expression signatures. Common signatures underwent pathway enrichment analysis and were then used to identify potential new pharmacological compounds via Integrative Library of Integrated Network-Based Cellular Signatures (iLINCS). Our search results yielded 5 AP-naive FEP studies and 4 early dysglycemia studies which met inclusion criteria. We discovered that AP-naive FEP and non-psychiatrically ill subjects exhibiting early dysglycemia shared 221 common signatures, which were enriched for pathways related to endoplasmic reticulum stress and abnormal brain energetics. Nine FDA-approved drugs were identified as potential drug treatments, of which the antidiabetic metformin, the first-line treatment for type 2 diabetes, has evidence to attenuate metabolic dysfunction in PSDs. Taken together, our findings support shared gene expression changes and biological pathways associating PSDs with dysglycemic disorders. These data suggest that the pathobiology of PSDs overlaps and potentially contributes to dysglycemia. Finally, we find that metformin may be a potential treatment for early metabolic dysfunction intrinsic to PSDs.

Objective Developing and evaluating new treatment guidelines for rheumatoid arthritis (RA) based on observational data requires a quantitative understanding of patterns in current treatment practice with biologic and targeted synthetic disease‐modifying antirheumatic drugs (b/tsDMARDs). Methods We used data from the CorEvitas RA registry to study patients starting their first b/tsDMARD therapy, defined as the first line of therapy, between 2012 and the end of 2021. We identified treatment patterns as unique sequences of therapy changes following and including the first‐line therapy. Therapy cycling was defined as switching back to a treatment from a previously used therapeutic class. Results A total of 6015 b/tsDMARD‐naïve patients (77% female) were included in the analysis. Their median age was 58 years, and their median disease duration was 3 years. In 2012–2014, 80% of the patients started a tumor necrosis factor inhibitor (TNFi) as their first b/tsDMARD. However, the use of TNFi decreased in favor of Janus kinase inhibitors since 2015. Although the number of treatment patterns was large, therapy cycling was relatively common. For example, 601 patterns were observed among 1133 patients who changed therapy at least four times, of whom 85.3% experienced therapy cycling. Furthermore, the duration of each of the first three lines of therapy decreased over the past decade. For example, the median duration of the first‐line therapy was 153 days in 2018–2021 compared to 208 days in 2015–2017 (P

Abstract In brain, the striatum is a heterogenous region involved in reward and goal-directed behaviors. Striatal dysfunction is linked to psychiatric disorders, including opioid use disorder (OUD). Striatal subregions are divided based on neuroanatomy, each with unique roles in OUD. In OUD, the dorsal striatum is involved in altered reward processing, formation of habits, and development of negative affect during withdrawal. Using single nuclei RNA-sequencing, we identified both canonical (e.g., dopamine receptor subtype) and less abundant cell populations (e.g., interneurons) in human dorsal striatum. Pathways related to neurodegeneration, interferon response, and DNA damage were significantly enriched in striatal neurons of individuals with OUD. DNA damage markers were also elevated in striatal neurons of opioid-exposed rhesus macaques. Sex-specific molecular differences in glial cell subtypes associated with chronic stress were found in OUD, particularly female individuals. Together, we describe different cell types in human dorsal striatum and identify cell type-specific alterations in OUD.

Abstract The yeast Saccharomyces cerevisiae is widely used as a host cell for recombinant protein production due to its fast growth, cost-effective culturing, and ability to secrete large and complex proteins. However, one major drawback is the relatively low yield of produced proteins compared to other host systems. To address this issue, we developed an overlay assay to screen the yeast knockout collection and identify mutants that enhance recombinant protein production, specifically focusing on the secretion of the Trametes trogii fungal laccase enzyme. Gene ontology analysis of these mutants revealed an enrichment of processes including vacuolar targeting, vesicle trafficking, proteolysis, and glycolipid metabolism. We confirmed that a significant portion of these mutants also showed increased activity of the secreted laccase when grown in liquid culture. Notably, we found that the combination of deletions of OCA6, a tyrosine phosphatase gene, along with PMT1 or PMT2, two genes encoding ER membrane protein-O-mannosyltransferases involved in ER quality control, and SKI3, which encode for a component of the SKI complex responsible for mRNA degradation, further increased secreted laccase activity. Conversely, we also identified over 200 gene deletions that resulted in decreased secreted laccase activity, including many genes that encode for mitochondrial proteins and components of the ER-associated degradation pathway. Intriguingly, the deletion of the ER DNAJ co-chaperone gene SCJ1 led to almost no secreted laccase activity. When we expressed SCJ1 from a low-copy plasmid, laccase secretion was restored. However, overexpression of SCJ1 had a detrimental effect, indicating that precise dosing of key chaperone proteins is crucial for optimal recombinant protein expression. This study offers potential strategies for enhancing the overall yield of recombinant proteins and provides new avenues for further research in optimizing protein production systems.

Abstract Background An increasing number of adults are over the age of 65, and there is concern about the increasing prevalence of age-associated cognitive decline and poor mental health status in older adults in the United States. Several nutrients are known to have important biological roles in brain health and neurological function, but many individuals fall short of recommended intake levels. The objective of this study was to examine the association between nutrient intake and cognitive function. We also explored whether nutrient intake was associated with depression. Methods This cross-sectional study was based on data from the National Health and Nutrition Examination Survey (NHANES) 2011–2014 and included participants ≥ 60 years of age who had reliable day 1 dietary recall data and either valid cognitive function data (n = 2713) or valid depression score data (n = 2943). The sample was stratified by gender, and cognitive functioning test (CFT) composite z-scores were analyzed by quartiles. Depression status was assessed using the Patient Health Questionnaire (PHQ-9). Results Higher intake and adequacy of a number of different nutrients from food were associated with higher cognitive function in both males and females. Nutrients that showed the most consistent associations with cognitive function across intake and adequacy analyses for food in both males and females were vitamin A, vitamin E, thiamin, riboflavin, vitamin B6, folate, magnesium, potassium, zinc, vitamin K, and lutein and zeaxanthin (p

Objective: To compare the perioperative, oncological, and functional outcomes between single-port robot-assisted radical prostatectomy (SP-RARP) and multiport robot-assisted radical prostatectomy (MP-RARP) via a meta-analysis. Methods: For relevant articles, three electronic databases, including PubMed, Scopus, and Web of Science, were searched from their inception until January 15, 2022. A meta-analysis has been reported in line with PRISMA 2020 and AMSTAR Guidelines. The risk ratio and weighted mean difference (MD) were applied for the comparison of dichotomous and continuous variables with 95% confidence intervals (CI). Results: Of the 368 retrieved abstracts, 41 underwent full-text review, and seven studies were included in the final analysis, comprising a total cohort of 1,934 cases of RARP (355 SP-RARP cases and 1,579 MP-RARP cases). Compared to MP-RARP, the SP-RARP group had less postoperative pain score (MD = –0.7, 95% CI –1 to –0.4, P

Abstract Introduction In this case report, we demonstrate our technique of a retroperitoneal laparoscopic heminephrectomy for a T1b right hilar tumor in a horseshoe kidney. Case presentation A 77-year-old Vietnamese woman presented to the hospital because of right flank pain. On presentation, her serum creatinine was 0.86 mg/dL and glomerular filtration rate was 65.2 mL/minute/1.73 m2. According to her renal scintigraphy, glomerular filtration rates of the right and left moieties were 24.2 and 35.5 mL/minute, respectively. Computed tomography imaging demonstrated a 5.5 × 5.0 cm solid hilar mass with a cT1bN0M0 tumor stage was in the right moiety. After discussion, the patient elected a minimally invasive surgery to treat her malignancy. The patient was placed in a flank position. We used Gaur’s balloon technique to create the retroperitoneal working space, and four trocar ports were planned for operation. Three arteries were dissected, including two arteries feeding the right moiety, one artery feeding the isthmus, and one vein, which was clipped and divided by Hem-o-lok. The isthmusectomy was performed with an Endostapler. Consequently, the ureter was clipped and divided. Finally, the whole right segment of the horseshoe kidney was mobilized and taken out via the flank incision. Results The total operative time was 250 min with an estimated blood loss of 200 mL. The patient's serum creatinine after surgery was 1.08 mg/dL, and glomerular filtration rate was 49.47 mL/minute/1.73 m2. The patient was discharged on postoperative day #4 without complication. Final pathologic examination of the tumor specimen revealed a Fuhrman grade II clear cell renal cell carcinoma, capsular invasion, with negative surgical margins. After a three-month follow-up, the serum creatinine was 0.95 mg/dL, and glomerular filtration rate was 57.7 mL/minute/1.73 m2. Local recurrence or metastasis was not detected by follow-up computed tomography imaging. Conclusions Retroperitoneal laparoscopic heminephrectomy is a safe and feasible technique for patients with renal cell carcinoma in a horseshoe kidney and may be particularly useful in low income settings without access to robotic technology.

This case study investigated a modern language teacher candidate’s developing translanguaging stance in a Masters-level TESOL course as she made sense of emerging tensions while drawing on her personal and teaching experiences. Data included the participant’s oral contributions to the course, the course syllabus, and student-produced artifacts. We used thematic analysis focusing on the participant’s perceptions of translanguaging as both theory and practice to analyze the data. A semi-structured interview was carried out five years later to review the impact of translanguaging on the participant’s teaching and ideology as a Spanish teacher in a dual language program. Findings uncovered five primary themes all related to the participant’s biographically related development of translanguaging stance: traditional second language acquisition theories as a concern, updating the notion of social justice, the ability to support positive identity development, contemplating translanguaging as a pedagogy, and the longevity of the biographical approach to lifelong learning. The findings highlight the importance of biographical approaches to lifelong learning in language education and suggest that teachers can foster bilingual development, establish inclusive teaching strategies, and create equitable language learning spaces by recognizing the potential of translanguaging, which may be made possible by fostering similar contexts in teacher education courses.

The world is becoming increasingly urbanized, with migration rates often exceeding the infra-structural capacity in cities across the developing world. As such, many migrants must reside in informal settlements that lack civil and health protection infrastructure, including air quality monitoring. Here, geospatial inverse distance weighting and archived Central Pollution Control Board (CPCB) air quality data for neighboring stations from 2018 to 2021 were used to estimate air conditions in five informal settlements in Delhi, India, spanning the 2020 pandemic lockdown. The results showed that WHO limits for PM2.5 and NO2 were exceeded regularly, although air quality improved during the pandemic. Air quality was always better during the monsoon season (44.3 ± 3.47 and 26.9 ± 2.35 μg/m3 for PM2.5 and NO2, respectively) and poorest in the post-monsoon season (180 ± 15.5 and 55.2 ± 3.59 μg/m3 for PM2.5 and NO2). Differences in air quality among settlements were explained by the proximity to major roads and places of open burning, with NO2 levels often being greater near roads and PM2.5 levels being elevated near places with open burning. Field monitoring was performed in 2023 at three settlements and local CPCB stations. Air quality at settlements and their closest station were not significantly different (p < 0.01). However, field data showed that on-site factors within settlements, such as cooking, ad hoc burning, or micro-scale industry, impact air quality on local scales, suggesting health risks are greater in informal settlements because of greater unregulated activity. City-scale models can estimate mean air quality concentrations at unmonitored locations, but caution is needed because such models can miss local exposures that may have the greatest impact on local health.

Lymphangioleiomyomatosis (LAM) is a rare genetic lung disease. Unfortunately, treatment with the mTORC1 inhibitor Rapamycin only slows disease progression, and incomplete responses are common. Thus, there remains an urgent need to identify new targets for the development of curative LAM treatments. Nitazoxanide (NTZ) is an orally bioavailable antiprotozoal small molecule drug approved for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum in children and adults, with a demonstrated mTORC1 inhibitory effect in several human cell lines. NTZ’s excellent safety profile characterized by its more than 20 years of clinical use makes it a promising candidate for repurposing. Our rationale for this study was to further investigate NTZ’s effect using in vitro and in vivo LAM models and to elucidate the underlying molecular mechanism beyond mTORC1 inhibition. For this purpose, we investigated cell proliferation, cell viability, and changes in protein phosphorylation and expression in primary human cell cultures derived from LAM lung samples before translating our results into a syngeneic mouse model utilizing Tsc2-null cells. NTZ reduced cell growth for all tested cell lines at a dose of about 30 µM. Lower doses than that had no effect on cell viability, but doses above 45 µM lowered the viability by about 10 to 15% compared to control. Interestingly, our western blot revealed no inhibition of mTORC1 and only a mild effect on active ß-Catenin. Instead, NTZ had a pronounced effect on reducing pAkt. In the mouse model, prophylactic NTZ treatment via the intraperitoneal and oral routes had some effects on reducing lung lesions and improving body weight retention, but the results remain inconclusive.

Abstract Western, northern, Mexican, and southern corn rootworms (WCR, NCR, MCR, and SCR) are serious corn pests. We evaluated host search behavior of these pests on six plant species using a video tracking system. After a 5-min exposure to plant roots, behavioral parameters were automatically recorded and used to quantify the search behavior. The search behavior was not observed for sorghum since no neonates survived after contacting sorghum roots. After exposures to corn roots, all neonates exhibited the localized search behaviors (i.e., shortening total distance traveled, lowering movement speed, increasing turn angle, moving farther from origin) which are used to stay in and search within root systems. When larvae contacted roots of wheat, barley, oats, soybean, or controls, they expanded the search area by extending the travel path, increasing velocity, and reducing turn angles and total distance moved. The intensity of the search expansion is highly associated with the host preferences known for the four rootworm species and subspecies. Neonates of each corn rootworm exhibited distinct search behaviors. In fact, NCR larvae had the highest speed, the greatest travel path, and the lowest turn angle, whereas MCR larvae had the highest turn angle and moved faster than WCR and SCR larvae.

Abstract Background Social affinity and collective behavior are nearly ubiquitous in the animal kingdom, but many lineages feature evolutionarily asocial species. These solitary species may have evolved to conserve energy in food-sparse environments. However, the mechanism by which metabolic shifts regulate social affinity is not well investigated. Results In this study, we used the Mexican tetra (Astyanax mexicanus), which features riverine sighted surface (surface fish) and cave-dwelling populations (cavefish), to address the impact of metabolic shifts on asociality and other cave-associated behaviors in cavefish, including repetitive turning, sleeplessness, swimming longer distances, and enhanced foraging behavior. After 1 month of ketosis-inducing ketogenic diet feeding, asocial cavefish exhibited significantly higher social affinity, whereas social affinity regressed in cavefish fed the standard diet. The ketogenic diet also reduced repetitive turning and swimming in cavefish. No major behavioral shifts were found regarding sleeplessness and foraging behavior, suggesting that other evolved behaviors are not largely regulated by ketosis. We further examined the effects of the ketogenic diet via supplementation with exogenous ketone bodies, revealing that ketone bodies are pivotal molecules positively associated with social affinity. Conclusions Our study indicated that fish that evolved to be asocial remain capable of exhibiting social affinity under ketosis, possibly linking the seasonal food availability and sociality.

Abstract Introduction Daptomycin doses 8–12 mg/kg are recommended for susceptible dose-dependent Enterococcus species. However, data remain limited on safety outcomes of such dosing, compared to standard 4–6 mg/kg dosing. Methods In this retrospective cohort study, patients were stratified into daptomycin standard-dose (≤ 6.5 mg/kg) versus high-dose (≥ 7.5 mg/kg) groups. The primary outcome was daptomycin safety based on a composite of creatine kinase elevation, daptomycin-related peripheral blood eosinophilia, eosinophilic pneumonitis, alanine aminotransferase elevation, and alkaline phosphatase elevation. A secondary aim was to identify risk factors for daptomycin adverse effects. Inclusion criteria were age ≥ 18 years old, daptomycin receipt for ≥ 48 h, and Enterococcus cultures with a daptomycin minimal inhibitory concentration 2–4 mg/L. Results A total of 119 patients were included for analysis. Median daptomycin doses were 6.0 mg/kg (IQR 5.4, 6.1) and 8.1 mg/kg (IQR 7.9, 9.6) in the standard- and high-dose cohorts, respectively. Median durations were 13.5 days (standard-dose) and 16 days (high-dose) (p = 0.02). The composite safety endpoint occurred in 32.0% of the standard-dose group and 32.5% of the high-dose group (p = 0.96). Daptomycin was dose-reduced or held in 8.1% of patients experiencing an adverse effect. Concurrent antihistamine usage was associated with the composite outcome; however, there was no association with daptomycin dose or concurrent statin use. Conclusion High-dose daptomycin was not associated with increased laboratory abnormalities or adverse drug reactions compared to standard-dose daptomycin.

A fundamental goal of modern-day astrophysics is to understand the connection between supermassive black hole (SMBH) growth and galaxy evolution. Merging galaxies offer one of the most dramatic channels for galaxy evolution known, capable of driving inflows of gas into galactic nuclei, potentially fueling both star formation and central SMBH activity. Dual active galactic nuclei (dual AGNs) in late-stage mergers with nuclear pair separations 10 keV) studies offer a relatively contamination-free tool for probing the dense obscuring environments predicted to surround the majority of dual AGN in late-stage mergers. To date, only a handful of the brightest and closest systems have been studied at these energies due to the demanding instrumental requirements involved. We demonstrate the unique capabilities of HEX-P to spatially resolve the soft and - for the first time - hard X-ray counterparts of closely-separated (∼2″−5″) dual AGNs in the local Universe. By incorporating physically-motivated obscuration models, we reproduce realistic broadband X-ray spectra expected for deeply embedded accreting SMBHs. Hard X-ray spatially resolved observations of dual AGNs—accessible only to HEX-P—will hence transform our understanding of dual AGN in the nearby Universe.

IMPORTANCE:. A recent study showed an association between high hospital-level noninvasive positive pressure ventilation (NIPPV) use and in-hospital cardiac arrest (IHCA) in children with bronchiolitis. OBJECTIVES:. We aimed to determine if patient-level exposure to NIPPV in children with bronchiolitis was associated with IHCA. DESIGN, SETTING AND PARTICIPANTS:. Retrospective cohort study at a single-center quaternary PICU in North America including children with International Classification of Diseases primary or secondary diagnoses of bronchiolitis in the Virtual Pediatric Systems database. MAIN OUTCOMES AND MEASURES:. The primary exposure was NIPPV and the primary outcome was IHCA. MEASUREMENTS AND MAIN RESULTS:. Of 4698 eligible ICU admissions with bronchiolitis diagnoses, IHCA occurred in 1.2% (57/4698). At IHCA onset, invasive mechanical ventilation (IMV) was the most frequent level of respiratory support (65%, 37/57), with 12% (7/57) receiving NIPPV. Patients with IHCA had higher Pediatric Risk of Mortality-III scores (3 [0–8] vs. 0 [0–2]; p < 0.001), more frequently had a complex chronic condition (94.7% vs. 46.2%; p < 0.001), and had higher mortality (21.1% vs. 1.0%; p < 0.001) compared with patients without IHCA. Return of spontaneous circulation (ROSC) was achieved in 93% (53/57) of IHCAs; 79% (45/57) survived to hospital discharge. All seven children without chronic medical conditions and with active bronchiolitis symptoms at the time of IHCA achieved ROSC, and 86% (6/7) survived to discharge. In multivariable analysis restricted to patients receiving NIPPV or IMV, NIPPV exposure was associated with lower odds of IHCA (adjusted odds ratio [aOR], 0.07; 95% CI, 0.03–0.18) compared with IMV. In secondary analysis evaluating categorical respiratory support in all patients, compared with IMV, NIPPV was associated with lower odds of IHCA (aOR, 0.35; 95% CI, 0.14–0.87), whereas no difference was found for minimal respiratory support (none/nasal cannula/humidified high-flow nasal cannula [aOR, 0.56; 95% CI, 0.23–1.36]). CONCLUSIONS AND RELEVANCE:. Cardiac arrest in children with bronchiolitis is uncommon, occurring in 1.2% of bronchiolitis ICU admissions. NIPPV use in children with bronchiolitis was associated with lower odds of IHCA.

Purpose: To examine the relationship between tibial tubercle–trochlear groove (TT-TG) distance and patellar tendon length. Methods: All healthy athletes who underwent anterior cruciate ligament reconstruction who had a magnetic resonance imaging (MRI) study of the knee on file between July 2018 and June 2019 at a single institution were retrospectively reviewed. Exclusion criteria included patients without an MRI study of the knee on file or with an MRI of insufficient quality precluding reliable calculation of TT-TG and patellar tendon length. MRIs were reviewed to calculate TT-TG, patellar tendon length, and Caton–Deschamps Index (CDI). Patient charts were reviewed to obtain anthropometric characteristics including sex, concomitant injuries, and previous knee procedures as well as age at time of MRI. Spearman correlations were used to assess the relationship between TT-TG, patellar tendon length, and CDI, with regression analysis performed to assess for relationships between TT-TG, patellar tendon length, and patient-specific factors. Results: Overall, 235 patients (99 female [42.1%], 136 male [57.9%]; mean age: 30.0 years [23.0; 40.0]) were included. Inter-rater reliability between the 2 reviewers was 0.888 for TT-TG, 0.804 for patellar tendon length, and 0.748 for CDI, indicating strong agreement. The correlation between TT-TG and patellar tendon length was 0.021, indicating no true relationship. The correlation between TT-TG and CDI was –0.048 and that of patellar tendon length and CDI was 0.411, indicating a weak positive relationship. Regression analysis found that male sex is strongly correlated with a longer patellar tendon length (odds ratio 2.65, 95% confidence interval 1.33-3.97, P < .001). Conclusions: In this study, no correlation was found between TT-TG and patellar tendon length or CDI. Male sex was correlated with a longer patellar length. Clinical Relevance: TT-TG does not appear to be a useful preoperative indicator of patellar tendon length and likely does not hold substantial value in preoperative templating of BTB graft sizes.

The Wolf Creek Conferences on Cardiac Arrest Resuscitation began in 1975, and have served as an important forum for thought leaders and scientists from industry and academia to come together with the common goal of advancing the field of cardiac arrest resuscitation. The Wolf Creek XVII Conference was hosted by the Max Harry Weil Institute of Critical Care Research and Innovation in Ann Arbor, Michigan on June 14–17, 2023. A new component of the conference was the Wolf Creek Innovator in Cardiac Arrest and Resuscitation Science Award competition. The competition was designed to recognize early career investigators from around the world who’s science is challenging the current paradigms in the field. Finalists were selected by a panel of international experts and invited to present in-person at the conference. The winner was chosen by electronic vote of conference participants and awarded a $10,0000 cash prize. Finalists included Carolina Barbosa Maciel from the University of Florida, Adam Gottula from the University of Michigan, Rajat Kalra from the University of Minnesota, Ryan Morgan from the Children’s Hospital of Philadelphia, Mitsuaki Nishikimi form Hiroshima University, and Jacob Sunshine from the University of Washington. Ryan Morgan from the Children’s Hospital of Philadelphia was selected as the 2023 Wolf Creek Innovator Awardee. This manuscript provides a summary of the work presented by each of the finalists and provides a preview of the future of resuscitation science.

Objectives To describe injury frequency and characteristics in roundnet athletes and compare injury characteristics between elite and non-elite athletes.Methods This cross-sectional study was performed by convenience sampling recreational and competitive roundnet athletes via a REDCap survey distributed through social media platforms. The custom survey evaluated athlete demographics, past sport participation, training workload and roundnet-related injuries throughout their whole playing career. Injury characteristics were reported for the full study cohort and compared between elite and non-elite athletes.Results 166 athletes participated in the study, with 33.7% playing at the elite level. 279 injuries were reported, with 86.1% (n=143) of athletes reporting at least one injury throughout their playing career. Injuries most frequently involved the shoulder (20%), ankle (18%), knee (14%) and elbow (14%). 47% of reported injuries occurred due to overuse, and 67% resulted in missed competition time averaging 2.0 months. There were 10 injuries (3.6%) that required surgery. No differences were found in regards to injury frequency (1.9±1.5 vs 1.6±1.1 injuries per athlete, p=0.159) or any injury characteristics between elite and non-elite athletes.Conclusion Roundnet athletes experienced a mean of 1.7±1.2 injuries while playing roundnet. Injuries most frequently involved the shoulder and ankle and often resulted in missed competition time. The level of competition does not significantly impact injury frequency or characteristics. Roundnet athletes may benefit from injury prevention programmes that include shoulder strengthening, maintaining shoulder range of motion and ankle stability.

Abstract Understanding the chemistry underpinning intermetallic synergy and the discovery of generally applicable structure-performances relationships are major challenges in catalysis. Additionally, high-performance catalysts using earth-abundant, non-toxic and inexpensive elements must be prioritised. Here, a series of heterodinuclear catalysts of the form Co(III)M(I/II), where M(I/II) = Na(I), K(I), Ca(II), Sr(II), Ba(II) are evaluated for three different polymerizations, by assessment of rate constants, turn over frequencies, polymer selectivity and control. This allows for comparisons of performances both within and between catalysts containing Group I and II metals for CO2/propene oxide ring-opening copolymerization (ROCOP), propene oxide/phthalic anhydride ROCOP and lactide ring-opening polymerization (ROP). The data reveal new structure-performance correlations that apply across all the different polymerizations: catalysts featuring s-block metals of lower Lewis acidity show higher rates and selectivity. The epoxide/heterocumulene ROCOPs both show exponential activity increases (vs. Lewis acidity, measured by the pK a of [M(OH2)m]n+), whilst the lactide ROP activity and CO2/epoxide selectivity show linear increases. Such clear structure-activity/selectivity correlations are very unusual, yet are fully rationalised by the polymerization mechanisms and the chemistry of the catalytic intermediates. The general applicability across three different polymerizations is significant for future exploitation of catalytic synergy and provides a framework to improve other catalysts.

Abstract Background Numerous studies have demonstrated that the increasing racial and ethnic diversity of the US population benefits from access to healthcare providers from similarly diverse backgrounds. Physician assistant (PA) education programs have striven to increase the diversity of the profession, which is predominantly non-Hispanic white, by focusing on admitting students from historically excluded populations. However, strategies such as holistic admissions are predicated on the existence of racially and ethnically diverse applicant pools. While studies have examined correlates of matriculation into a medical education program, this study looks earlier in the pipeline and investigates whether applicant – not matriculant – pool diversity varies among PA programs with different characteristics. Methods Data were drawn from the 2017–2018 Central Application Service for PAs admissions cycle. Applications to programs with pre-professional tracks and applicants missing race/ethnicity data were excluded, resulting in data from 26,600 individuals who applied to 189 PA programs. We summarized the racial and ethnic diversity of each program’s applicant pools using: [1]the proportion of underrepresented minority (URM) students, [2]the proportion of students with backgrounds underrepresented in medicine (URiM), and [3]Simpson’s diversity index of a 7-category race/ethnicity combination. We used multiple regressions to model each diversity metric as a function of program characteristics including class size, accreditation status, type of institution, and other important features. Results Regardless of the demographic diversity metric examined, we found that applicant diversity was higher among provisionally accredited programs and those receiving more applications. We also identified trends suggesting that programs in more metropolitan areas were able to attract more diverse applicants. Programs that did not require the GRE were also able to attract more diverse applicants when considering the URM and SDI metrics, though results for URiM were not statistically significant. Conclusions Our findings provide insights into modifiable (e.g., GRE requirement) and non-modifiable (e.g., provisionally accredited) program characteristics that are associated with more demographically diverse applicant pools.

Abstract Proximal spinal muscular atrophy (SMA) is a leading genetic cause for infant death in the world and results from the selective loss of motor neurons in the spinal cord. SMA is a consequence of low levels of SMN protein and small molecules that can increase SMN expression are of considerable interest as potential therapeutics. Previous studies have shown that both 4-phenylbutyrate (4PBA) and trichostatin A (TSA) increase SMN expression in dermal fibroblasts derived from SMA patients. AR42 is a 4PBA-tethered TSA derivative that is a very potent histone deacetylase inhibitor. SMA patient fibroblasts were treated with either AR42, AR19 (a related analogue), 4PBA, TSA or vehicle for 5 days and then immunostained for SMN localization. AR42 as well as 4PBA and TSA increased the number of SMN-positive nuclear gems in a dose-dependent manner while AR19 did not show marked changes in gem numbers. While gem number was increased in AR42-treated SMA fibroblasts, there were no significant changes in FL-SMN mRNA or SMN protein. The neuroprotective effect of this compound was then assessed in SMNΔ7 SMA (SMN2 +/+ ;SMNΔ7 +/+ ;mSmn −/− ) mice. Oral administration of AR42 prior to disease onset increased the average lifespan of SMNΔ7 SMA mice by ~ 27% (20.1 ± 1.6 days for AR42-treated mice vs. 15.8 ± 0.4 days for vehicle-treated mice). AR42 treatment also improved motor function in these mice. AR42 treatment inhibited histone deacetylase (HDAC) activity in treated spinal cord although it did not affect SMN protein expression in these mice. AKT and GSK3β phosphorylation were both significantly increased in SMNΔ7 SMA mouse spinal cords. In conclusion, presymptomatic administration of the HDAC inhibitor AR42 ameliorates the disease phenotype in SMNΔ7 SMA mice in a SMN-independent manner possibly by increasing AKT neuroprotective signaling.

Abstract Targeting protein for Xklp2 (TPX2) is a key factor that stimulates branching microtubule nucleation during cell division. Upon binding to microtubules (MTs), TPX2 forms condensates via liquid-liquid phase separation, which facilitates recruitment of microtubule nucleation factors and tubulin. We report the structure of the TPX2 C-terminal minimal active domain (TPX2α5-α7) on the microtubule lattice determined by magic-angle-spinning NMR. We demonstrate that TPX2α5-α7 forms a co-condensate with soluble tubulin on microtubules and binds to MTs between two adjacent protofilaments and at the intersection of four tubulin heterodimers. These interactions stabilize the microtubules and promote the recruitment of tubulin. Our results reveal that TPX2α5-α7 is disordered in solution and adopts a folded structure on MTs, indicating that TPX2α5-α7 undergoes structural changes from unfolded to folded states upon binding to microtubules. The aromatic residues form dense interactions in the core, which stabilize folding of TPX2α5-α7 on microtubules. This work informs on how the phase-separated TPX2α5-α7 behaves on microtubules and represents an atomic-level structural characterization of a protein that is involved in a condensate on cytoskeletal filaments.