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When to allow an athlete to return to unrestricted sporting activity after anterior cruciate ligament (ACL) reconstruction remains controversial.To report the results of functional performance testing reported in the literature for individuals at differing

Abstract Venetoclax is a promising drug for patients with acute myeloid leukemia (AML) ineligible for anthracycline-based treatments. In rats, venetoclax is reported to cause myocardial injury. Our objectives were to report the frequency of cardiovascular (CV) events in patients treated with venetoclax, and, subsequently, to compare CV outcomes in matched patients treated with venetoclax or anthracyclines. Patients diagnosed with AML and treated with venetoclax or anthracyclines from January 2017 to July 2021 were identified. Major adverse cardiac events (MACE, including new-onset heart failure (HF), acute myocardial infarction, new onset atrial fibrillation (AF)) were recorded. Propensity-score method was then used to compare patients treated with venetoclax or anthracyclines. Patients treated with venetoclax (n=103) were older, with more hyperlipidemia than patients treated with anthracyclines (n=217). However, only 63% of patients treated with venetoclax underwent echocardiographic screening (vs. 93% of patients treated with anthracyclines, P< 0.001). Eighteen patients with venetoclax (17%) and 27 patients with anthracyclines (12%) developed MACE, including 10 % of new HF in each group. The median time to MACE was 8 days (interquartile range 5-98 days). In the matched cohort (n=132 patients), the cumulative incidence of MACE at one year was not different (17.5 % venetoclax, 9.2% anthracyclines, p =0.27). Thus, MACE incidence is similar in matched patients receiving venetoclax or anthracyclines. Close CV monitoring during the early phase of treatment may be helpful in patients treated with venetoclax.

Abstract Torpor encompasses diverse adaptations to extreme environmental stressors such as hibernation, aestivation, brumation, and daily torpor. Here we introduce StrokeofGenus, an analytic pipeline that identifies distinct transcriptomic states and shared gene expression patterns across studies, tissues, and species. We use StrokeofGenus to study multiple and diverse forms of torpor from publicly-available RNA-seq datasets that span eight species and two classes. We identify three transcriptionally distinct states during the cycle of heterothermia: euthermia, torpor, and interbout arousal. We also identify torpor-specific gene expression patterns that are shared both across tissues and between species with over three hundred million years of evolutionary divergence. We further demonstrate the general sharing of gene expression patterns in multiple forms of torpor, implying a common evolutionary origin for this process. Although here we apply StrokeofGenus to analysis of torpor, it can be used to interrogate any other complex physiological processes defined by transient transcriptomic states.

Abstract Maize is the most grown feed crop in the United States. Due to wind storms and other factors, 5% of maize falls over annually. The longitudinal shear modulus of maize stalk tissues is currently unreported and may have a significant influence on stalk failure. To better understand the causes of this phenomenon, maize stalk material properties need to be measured so that they can be used as material constants in computational models that provide detailed analysis of maize stalk failure. This study reports longitudinal shear modulus of maize stalk tissue through repeated torsion testing of dry and fully mature maize stalks. Measurements were focused on the two tissues found in maize stalks: the hard outer rind and the soft inner pith. Uncertainty analysis and comparison of multiple methodologies indicated that all measurements are subject to low error and bias. The results of this study will allow researchers to better understand maize stalk failure modes through computational modeling. This will allow researchers to prevent annual maize loss through later studies. This study also provides a methodology that could be used or adapted in the measurement of tissues from other plants such as sorghum, sugarcane, etc.

Abstract Many parts of the world face severe and prolonged drought conditions, stressing the sustainability of water resources and agriculture. Transitioning to water-efficient crops is one strategy that can help adapt to water scarcity. An emerging drought-tolerant crop of interest is chia (Salvia hispanica). Yet, no study has compared its large-scale water use dynamics to those of widely established crops across the globe. Here, we use satellite data over multiple years to assess the water use efficiency of chia, alfalfa, corn, and soybean globally. Results show that chia consumed 13-38% less water than alfalfa, corn, and soy and assimilated 14-20% more carbon per amount of water used. Substituting 10% of Southwest United States alfalfa cultivation with chia would save 184 million liters of water per growing season, equivalent to the annual water consumption of 1,300 households. Future research shall explore the economic, societal, and environmental ramifications of substituting alfalfa with chia in dry areas worldwide. These insights can guide decision-makers in promoting sustainable agriculture and water resource management.

Abstract Background Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects. Methods We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. Results Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects. Conclusions This work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

Abstract Health risks due to preventable infections such as human papillomavirus (HPV) are exacerbated by persistent vaccine hesitancy. Due to limited sample sizes and the time needed to roll out, traditional methodologies like surveys and interviews offer restricted insights into quickly evolving vaccine concerns. Social media platforms can serve as fertile ground for monitoring vaccine-related conversations and detecting emerging concerns in a scalable and dynamic manner. Using state-of-the-art large language models, we propose a minimally supervised end-to-end approach to identify concerns against HPV vaccination from social media posts. We detect and characterize the concerns against HPV vaccination pre- and post-2020 to understand the evolution of HPV vaccine discourse. Upon analyzing 653 k HPV-related post-2020 tweets, adverse effects, personal anecdotes, and vaccine mandates emerged as the dominant themes. Compared to pre-2020, there is a shift towards personal anecdotes of vaccine injury with a growing call for parental consent and transparency. The proposed approach provides an end-to-end system, i.e. given a collection of tweets, a list of prevalent concerns is returned, providing critical insights for crafting targeted interventions, debunking messages, and informing public health campaigns.

Abstract The increased use of biofuels in place of fossil fuels is one strategy to support the transition to net-zero carbon emissions, particularly in transport applications. However, expansion of the use of 1st generation crops as feedstocks is unsustainable due to the conflict with food use. The use of the lignocellulosic fractions from plants and/or co-products from food production including food wastes could satisfy the demand for biofuels without affecting the use of land and the availability of food, but organisms which can readily ferment all the carbohydrates present in these feedstocks often suffer from more severe bioethanol inhibition effects than yeast. This paper demonstrates the potential of hot gas microbubbles to strip ethanol from a thermophilic fermentation process using Parageobacillus thermoglucosidasius TM333, thereby reducing product inhibition and allowing production to continue beyond the nominal toxic ethanol concentrations of ≤ 2% v/v. Using an experimental rig in which cells were grown in fed-batch cultures on sugars derived from waste bread, and the broth continuously cycled through a purpose-built microbubble stripping unit, it was shown that non/low-inhibitory dissolved ethanol concentrations could be maintained throughout, despite reaching productivities equivalent to 4.7% v/v dissolved ethanol. Ethanol recovered in the condensate was at a concentration appropriate for dewatering to be cost effective and not prohibitively energy intensive. This suggests that hot microbubble stripping could be a valuable technology for the continuous production of bioethanol from fermentation processes which suffer from product inhibition before reaching economically viable titres, which is typical of most thermophilic ethanologenic bacteria.

AlScN is a new wide bandgap, high-k, ferroelectric material for radio frequency (RF), memory, and power applications. Successful integration of high-quality AlScN with GaN in epitaxial layer stacks depends strongly on the ability to control lattice parameters and surface or interface through growth. This study investigates the molecular beam epitaxy growth and transport properties of AlScN/GaN multilayer heterostructures. Single-layer Al1−xScxN/GaN heterostructures exhibited lattice-matched composition within x = 0.09–0.11 using substrate (thermocouple) growth temperatures between 330 and 630 °C. By targeting the lattice-matched Sc composition, pseudomorphic AlScN/GaN multilayer structures with ten and twenty periods were achieved, exhibiting excellent structural and interface properties as confirmed by x-ray diffraction (XRD) and scanning transmission electron microscopy (STEM). These multilayer heterostructures exhibited substantial polarization-induced net mobile charge densities of up to 8.24 × 1014/cm2 for twenty channels. The sheet density scales with the number of AlScN/GaN periods. By identifying lattice-matched growth condition and using it to generate multiple conductive channels, this work enhances our understanding of the AlScN/GaN material platform.

Objectives: The Australian Government, through the National Obesity Strategy 2022–2032, has set an aspirational goal of reducing the prevalence of childhood and adolescent overweight and obesity by 5% by 2030 (from 25% to 20%). Our objective was to quantify the long-term economic benefits of achieving this goal. Methods: Using a microsimulation model and a synthetic cohort of Australian children and adolescents aged 4–17 years, we estimated the excess per capita lifetime costs of overweight and obesity. Using these results and population projections for 2030, we estimated the potential lifetime cost savings that could be achieved through attaining the National Obesity Strategy goal. Results: Compared with their peers of a healthy weight, children and adolescents with overweight and obesity were estimated to incur, per capita, excess lifetime costs (discounted) of approximately $19 700 and $46 700, respectively (in 2030 Australian dollars). Achieving the National Obesity Strategy’s goal was estimated to save approximately $7.44 billion, predominantly through reductions in lifetime obesity-related healthcare costs and premature mortality. Conclusion: Our results demonstrate the considerable economic benefits that could be achieved by reducing the current prevalence of childhood and adolescent overweight and obesity in Australia; they provide justification for investment in prevention and treatment for this demographic.

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Background:. Nerve transfer procedures are performed in patients with proximal nerve injuries to optimize their potential for functional recovery. The study aimed to determine the preferred surgical technique and tool used by peripheral nerve surgeons to transect nerves in nerve transfers. Methods:. All current members of the American Society of Peripheral Nerve were invited to complete a cross-sectional 10-question survey. Data on practice demographics, nerve-cutting instruments/techniques used, and their belief on whether this impacted patient outcomes were collected. Results:. A total of 49 American Society of Peripheral Nerve members participated in the study, the majority of whom were over 10 years into practice (n = 30/49; 61%). The most common response was a scalpel blade (n = 26/49; 53%), with the remaining 47% using iris scissors, micro-serrated scissors, a razor blade, specialized nerve microscissors, or a specialized nerve-cutting device. The number of years in practice (P = 0.0271) and the percentage of practice that involves treating patients with peripheral nerve injuries (P = 0.0054) is significantly associated with the belief that crushing the donor nerves during transection may result in worse outcomes following nerve transfer. Only the latter is significantly associated with this belief in recipient nerves (P = 0.0214). Conclusions:. Our findings demonstrate that peripheral nerve surgeons believe that the technique used to transect nerves before coaptation influences outcomes after nerve transfer. Further ex vivo studies are necessary to investigate how different cutting techniques influence nerve morphology and scarring at the coaptation site to optimize outcomes after peripheral nerve surgery.

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to limited therapeutic options and expensive/burdensome drug discovery processes. Utilizing genomic-data-driven Connectivity Mapping (CMAP) to identify a drug closer to real-world PC targeting may improve pancreatic cancer (PC) patient outcomes. Initially, we mapped CMAP data to gene expression from 106 PC patients, identifying nine negatively connected drugs. These drugs were further narrowed down using a similar analysis for PC cell lines, human tumoroids, and patient-derived xenografts datasets, where ISOX emerged as the most potent agent to target PC. We used human and mouse syngeneic PC cells, human and mouse tumoroids, and in vivo mice to assess the ability of ISOX alone and in combination with 5FU to inhibit tumor growth. Global transcriptomic and pathway analysis of the ISOX-LINCS signature identified HDAC 6/cMyc as the target axis for ISOX. Specifically, we discovered that genetic and pharmacological targeting of HDAC 6 affected non-histone protein cMyc acetylation, leading to cMyc instability, thereby disrupting PC growth and metastasis by affecting cancer stemness. Finally, KrasG12D harboring tumoroids and mice responded effectively against ISOX and 5FU treatment by enhancing survival and controlling metastasis incidence. Overall, our data validate ISOX as a new drug to treat advanced PC patients without toxicity to normal cells. Our study supports the clinical utility of ISOX along with 5FU in future PC clinical trials.

Background Bongkrekic acid (BA) is a mitochondrial toxin, produced by the bacteria Burkholderia gladioli pv. cocovenenans during fermentation. Outbreaks of BA poisoning have been reported in China, Indonesia, and Mozambique, but have not been previously observed in North America.Case discussion A 67-year-old male with a past medical history of hypertension presented with two days of generalized weakness, nausea, and vomiting. He had consumed ogi, a home-fermented cornmeal pudding two days earlier. The patient developed acute liver failure, encephalopathy, acute kidney injury, coagulopathy, methemoglobinemia, and metabolic acidosis. Despite intensive care, he died on hospital day 8. Workup for common causes of acute liver failure was negative. Blood testing was positive for BA, estimated at 1,000 ng/mL. This case illustrates poisoning by BA, a rare and often lethal toxin resulting from improperly fermented food.

Tuberculosis (TB) is the foremost cause of infectious fatality globally. The primary global challenge in combatting TB lies in addressing the emergence of drug-resistant variants of the disease. However, the number of newly approved agents for treating TB has remained remarkably low over recent decades. Hence, research endeavors for discovering novel anti-TB agents are always needed. In the present study, we screened over 1,500 culture extracts from actinomycetes isolated in Indonesia for their inhibitory activity against Mycobacterium smegmatis used as a surrogate in the primary screening. The initial screening yielded approximately 6.2 % hit extracts, with a selection criterion of >80 % growth inhibition. The confirmed hit extracts were subsequently subjected to growth inhibition assay against Mycobacterium bovis and Mycobacterium tuberculosis. Approximately 20 % of the hit extracts that showed growth inhibition also exhibited efficacy against M. bovis BCG and M. tuberculosis H37Rv pathogenic strain. An active compound was successfully purified from a large-scale culture of the most potent representative extract by high-performance liquid chromatography and thin-layer chromatography. The structure of the active compound was elucidated by mass spectrometry and nuclear magnetic resonance. This compound displayed structural similarities to actinomycin group and exhibited robust inhibition, with IC50 values of 0.74, 0.02, and 0.07 μg/mL against M. smegmatis, M. bovis, and M. tuberculosis, respectively. The Actinomycetes strain A612, which produced the active compound, was taxonomically classified by phylogenetic analysis of 16s rRNA gene and whole genome sequencing data as Streptomyces parvus. Computational genome analysis utilizing anti-SMASH 7.0 unveiled that S. parvus A612 strain harbors 40 biosynthetic gene clusters with the potential to produce 16 known (with >70 % similarity) and 24 unknown compounds. A non-ribosomal peptide synthesis (NRPS) gene cluster associated with actinomycin D biosynthesis was also identified, boasting an 85 % similarity. Molecular docking analysis of actinomycin D and 21 potential M. tuberculosis targets revealed possible interactions with multiple targets. The purified active compound inhibited recombinant M. tuberculosis shikimate kinase (MtSK), which validated the results obtained from the docking analysis.

Background: Peak oxygen consumption and oxygen pulse along with their respective percent predicted measures are gold standards of exercise capacity. To date, no studies have investigated the relationship between percent predicted peak oxygen pulse (%PredO2P) and ventricular-vascular response (VVR) and the association of %PredO2P with all-cause mortality in heart failure with preserved ejection fraction (HFpEF) patients. Objectives: The authors investigated the association between: 1) CPET measures of %PredO2P and VVR; and 2) %PredO2P and all-cause mortality in HFpEF patients. Methods: Our cohort of 154 HFpEF patients underwent invasive CPET and were grouped into %PredO2P tertiles. The association between percent predicted Fick components and markers of VVR (ie, proportionate pulse pressure, effective arterial elastance) was determined with correlation analysis. The Cox proportional hazards model was used to identify predictors of mortality. Results: The participants’ mean age was 57 ± 15 years. Higher %PredO2P correlated with higher exercise capacity. In terms of VVR, higher %PredO2P correlated with a lower pressure for a given preload (effective arterial elastance r = −0.45, P

ABSTRACT Escherichia coli is the leading cause of urinary tract infections (UTIs) in children and adults. The gastrointestinal tract is the primary reservoir of uropathogenic E. coli, which can be acquired from a variety of environmental exposures, including retail meat. In the current study, we used a novel statistical-genomic approach to estimate the proportion of pediatric UTIs caused by foodborne zoonotic E. coli strains. E. coli urine isolates were collected from DC residents aged 2 months to 17 years from the Children’s National Medical Center Laboratory, 2013–2014. During the same period, E. coli isolates were collected from retail poultry products purchased from 15 sites throughout DC. A total of 52 urine and 56 poultry isolates underwent whole-genome sequencing, core genome phylogenetic analysis, and host-origin prediction by a Bayesian latent class model that incorporated data on the presence of mobile genetic elements (MGEs) among E. coli isolates from multiple vertebrate hosts. A total of 56 multilocus sequence types were identified among the isolates. Five sequence types—ST10, ST38, ST69, ST117, and ST131—were observed among both urine and poultry isolates. Using the Bayesian latent class model, we estimated that 19% (10/52) of the clinical E. coli isolates in our population were foodborne zoonotic strains. These data suggest that a substantial portion of pediatric UTIs in the Washington DC region may be caused by E. coli strains originating in food animals and likely transmitted via contaminated poultry meat.IMPORTANCEEscherichia coli UTIs are a heavy public health burden and can have long-term negative health consequences for pediatric patients. E. coli has an extremely broad host range, including humans, chickens, turkeys, pigs, and cattle. E. coli derived from food animals is a frequent contaminant of retail meat products, but little is known about the risk these strains pose to pediatric populations. Quantifying the proportion of pediatric UTIs caused by food-animal-derived E. coli, characterizing the highest-risk strains, and identifying their primary reservoir species could inform novel intervention strategies to reduce UTI burden in this vulnerable population. Our results suggest that retail poultry meat may be an important vehicle for pediatric exposure to zoonotic E. coli strains capable of causing UTIs. Vaccinating poultry against the highest-risk strains could potentially reduce poultry colonization, poultry meat contamination, and downstream pediatric infections.

Summary: Background: The clinical relevance of recurrent venous thromboembolism (VTE) after discontinuing anticoagulation in patients with COVID-19-associated VTE remains uncertain. We estimated the incidence rates and mortality of VTE recurrences developing after discontinuing anticoagulation in patients with COVID-19-associated VTE. Methods: A prospective, multicenter, non-interventional study was conducted between March 25, 2020, and July 26, 2023, including patients who had discontinued anticoagulation after at least 3 months of therapy. All patients from the registry were analyzed during the study period to verify inclusion criteria. Patients with superficial vein thrombosis, those who did not receive at least 3 months of anticoagulant therapy, and those who were followed for less than 15 days after discontinuing anticoagulation were excluded. Outcomes were: 1) Incidence rates of symptomatic VTE recurrences, and 2) fatal PE. The rate of VTE recurrences was defined as the number of patients with recurrent VTE divided by the patient-years at risk of recurrent VTE during the period when anticoagulation was discontinued. Findings: Among 1106 patients with COVID-19-associated VTE (age 62.3 ± 14.4 years; 62.9% male) followed-up for 12.5 months (p25-75, 6.3–20.1) after discontinuing anticoagulation, there were 38 VTE recurrences (3.5%, 95% confidence interval [CI]: 2.5–4.7%), with a rate of 3.1 per 100 patient-years (95% CI: 2.2–4.2). No patient died of recurrent PE (0%, 95% CI: 0–7.6%). Subgroup analyses showed that patients with diagnosis in 2021–2022 (vs. 2020) (Hazard ratio [HR] 2.86; 95% CI 1.45–5.68) or those with isolated deep vein thrombosis (vs. pulmonary embolism) (HR 2.31; 95% CI 1.19–4.49) had significantly higher rates of VTE recurrences. Interpretation: In patients with COVID-19-associated VTE who discontinued anticoagulation after at least 3 months of treatment, the incidence rate of recurrent VTE and the case-fatality rate was low. Therefore, it conceivable that long-term anticoagulation may not be required for many patients with COVID-19-associated VTE, although further research is needed to confirm these findings. Funding: Sanofi and Rovi, Sanofi Spain.

ABSTRACT Asexual replication in the apicomplexan Sarcocystis neurona involves two main developmental stages: the motile extracellular merozoite and the sessile intracellular schizont. Merozoites invade host cells and transform into schizonts that undergo replication via endopolygeny to form multiple (64) daughter merozoites that are invasive to new host cells. Given that the capabilities of the merozoite vary significantly from the schizont, the patterns of transcript levels throughout the asexual lifecycle were determined and compared in this study. RNA-Seq data were generated from extracellular merozoites and four intracellular schizont development time points. Of the 6,938 genes annotated in the S. neurona genome, 6,784 were identified in the transcriptome. Of these, 4,111 genes exhibited significant differential expression between the merozoite and at least one schizont development time point. Transcript levels were significantly higher for 2,338 genes in the merozoite and 1,773 genes in the schizont stages. Included in this list were genes encoding the secretory pathogenesis determinants (SPDs), which encompass the surface antigen and SAG-related sequence (SAG/SRS) and the secretory organelle proteins of the invasive zoite stage (micronemes, rhoptries, and dense granules). As anticipated, many of the S. neurona SPD gene transcripts were abundant in merozoites. However, several SPD transcripts were elevated in intracellular schizonts, suggesting roles unrelated to host cell invasion and the initial establishment of the intracellular niche. The hypothetical genes that are potentially unique to the genus Sarcocystis are of particular interest. Their conserved expression patterns are instructive for future investigations into the possible functions of these putative Sarcocystis-unique genes.IMPORTANCEThe genus Sarcocystis is an expansive clade within the Apicomplexa, with the species S. neurona being an important cause of neurological disease in horses. Research to decipher the biology of S. neurona and its host-pathogen interactions can be enhanced by gene expression data. This study has identified conserved apicomplexan orthologs in S. neurona, putative Sarcocystis-unique genes, and gene transcripts abundant in the merozoite and schizont stages. Importantly, we have identified distinct clusters of genes with transcript levels peaking during different intracellular schizont development time points, reflecting active gene expression changes across endopolygeny. Each cluster also has subsets of transcripts with unknown functions, and investigation of these seemingly Sarcocystis-unique transcripts will provide insights into the interesting biology of this parasite genus.

Abstract Compression sonography has been proposed as a method for non‐invasive measurement of venous pressures during spaceflight, but initial reports of venous pressure measured by compression ultrasound conflict with prior reports of invasively measured central venous pressure (CVP). The aim of this study is to determine the agreement of compression sonography of the internal jugular vein (IJVP) with invasive measures of CVP over a range of pressures relevant to microgravity exposure. Ten healthy volunteers (18–55 years, five female) completed two 3‐day sessions of supine bed rest to simulate microgravity. IJVP and CVP were measured in the seated position, and in the supine position throughout 3 days of bed rest. The range of CVP recorded was in line with previous reports of CVP during changes in posture on Earth and in microgravity. The correlation between IJVP and CVP was poor when measured during spontaneous breathing (r = 0.29; R2 = 0.09; P = 0.0002; standard error of the estimate (SEE) = 3.0 mmHg) or end‐expiration CVP (CVPEE; r = 0.19; R2 = 0.04; P = 0.121; SEE = 3.0 mmHg). There was a modest correlation between the change in CVP and the change in IJVP for both spontaneous ΔCVP (r = 0.49; R2 = 0.24; P

Aluminum scandium nitride (AlScN) has been receiving increasing interest for radio frequency microelectromechanical systems because of their higher achievable bandwidths owing to the larger piezoelectric response of AlScN compared to AlN. However, alloying scandium (Sc) with aluminum nitride (AlN) significantly lowers the thermal conductivity of AlScN due to phonon alloy scattering. Self-heating in AlScN devices potentially limits power handling, constrains the maximum transmission rate, and ultimately leads to thermal failure. We grew plasma-assisted molecular beam epitaxy (PAMBE) AlScN on AlN-Al2O3 and GaN-Al2O3 substrates, and compared the cross-plane thermal conductivity to current work on AlScN grown on Si substrates.

AbstractIntroduction: Whole Bowel Irrigation (WBI) is used as a method of gastrointestinal decontamination for poisoned patients and may have low compliance when recommended by poison centers (PC). We set out to determine WBI compliance and analyze trends and possible associations between WBI compliance and clinical outcomes. Methods: We conducted a single-center retrospective chart review of PC data from 1/1/2011 to 12/31/2019 and included cases in which WBI was recommended. We collected demographic data, exposure history, therapies recommended and performed, and clinical outcomes. Compliance rate was calculated. Chi-squared and Mann-Whitney U tests were performed to look for differences in compliance based on case characteristics such as compliance rate by year, compliance based medication ingested and presence of intubation. We also looked for a possible association between WBI compliance and clinical outcome. Results: Four hundred and eighty-three cases met inclusion criteria. Fifty-five percent of patients were male and the median age was 32.5 years. Compliance to WBI recommendations was 58.2%. There was no significant difference in compliance when comparing by age, gender, medication ingested, or year. There was no association between compliance to WBI and clinical outcomes. Conclusions: We calculated a compliance rate of 58% when WBI was recommended. Compliance to WBI does not appear to be associated with changes in clinical outcome.

L-cone opsin expression by gene therapy is a promising treatment for blue cone monochromacy (BCM) caused by congenital lack of long- and middle-wavelength-sensitive (L/M) cone function. Eight patients with BCM and confirmed pathogenic variants at the OPN1LW/OPN1MW gene cluster participated. Optical coherence tomography (OCT), chromatic perimetry, chromatic microperimetry, chromatic visual acuity (VA), and chromaticity thresholds were performed with unmodified commercial equipment and/or methods available in the public domain. Adaptive optics scanning laser ophthalmoscope (AOSLO) imaging was performed in a subset of patients. Outer retinal changes were detectable by OCT with an age-related effect on the foveal disease stage. Rod and short-wavelength-sensitive (S) cone functions were relatively retained by perimetry, although likely impacted by age-related increases in the pre-retinal absorption of short-wavelength lights. The central macula showed a large loss of red sensitivity on dark-adapted microperimetry. Chromatic VAs with high-contrast red gratings on a blue background were not detectable. Color vision was severely deficient. AOSLO imaging showed reduced total cone density with majority of the population being non-waveguiding. This study developed and evaluated specialized outcomes that will be needed for the determination of efficacy and safety in human clinical trials. Dark-adapted microperimetry with a red stimulus sampling the central macula would be a key endpoint to evaluate the light sensitivity improvements. VA changes specific to L-opsin can be measured with red gratings on a bright blue background and should also be considered as outcome measures in future interventional trials.

In 1944, the architect Antonio Gómez Davó designed and built a new house for Mr. Ferrer at Rocafort in the suburbs of Valencia (Spain). In this same year, Europe, America, Russia and even Japan were still at war and Spain was recovering from its own intestine conflict. Therefore, architectural innovations and influences were scarce, as was the circulation of specialized journals on the matter. Still, many creations were occurring, like ceramic vaults and the brise-soleil; further, the architect Le Corbusier had stated his profound nostalgia for the Mediterranean, a sea that he had come to appreciate in his travels to the “East”. In the case of Gómez Davó, having been born and raised in a prominent family of Valencia, he could not remain indifferent to the design features that appeared in the vernacular architecture of the area, especially the type of inclined louvers of Arabic descent, that covered bow-windows and balconies and which have come to be known in Spain as the Majorcan louvers; these are currently even employed by prominent architects like Rafael Moneo at the extension of the Painter Miro Foundation. However, with so many difficult circumstances surrounding him, Gómez Davó could not get to the point of producing a ground-breaking design based on solar assumptions for the whole façade of the house he was building; instead, when providing an entrance porch apt for living life in the pure Mediterranean tradition, he ventured to construct a surprising perforated wall oriented to the south in order to control radiation in the winter and provide shade in the summer while affording excellent light and superb conditions of ventilation. By means of self-devised simulation tools, we have analyzed the conditions of the house and especially of his innovative brise-soleil, which are at times reminiscent of Alvar Aalto’s solutions for day-lit roofs, and which he intuitively adapted to the latitude of Valencia with the help of incipient notions of solar geometry. By outlining such unknown and bold precedent and assessing the house’s proper climatic performance, we contribute to revitalizing the early and daring pioneers of solar architecture in peripheral Spain and Europe during the birth of critic regionalism, a fact often disregarded in the conventional history of Modern Architecture.

Approximately 50% of patients diagnosed with ovarian cancer harbor tumors with mutations in BRCA1, BRCA2, or other genes involved in homologous recombination repair (HR). The presence of homologous recombination deficiency (HRD) is an approved biomarker for poly-ADP-ribose polymerase inhibitors (PARPis) as a maintenance treatment following a positive response to initial platinum-based chemotherapy. Despite this treatment option, the development of resistance to PARPis is common among recurrent disease patients, leading to a poor prognosis. In this study, we conducted a comprehensive analysis using publicly available datasets to elucidate the molecular mechanisms driving PARPi resistance in BRCA1-deficient ovarian cancer. Our findings reveal a central role for the interferon (IFN) pathway in mediating resistance in the context of BRCA1 deficiency. Through integrative bioinformatics approaches, we identified LY6E, an interferon-stimulated gene, as a key mediator of PARPi resistance, with its expression linked to an immunosuppressive tumor microenvironment (TME) encouraging tumor progression and invasion. LY6E amplification correlates with poor prognosis and increased expression of immune-related gene signatures, which is predictive of immunotherapy response. Interestingly, LY6E expression upon PARPi treatment resistance was found to be dependent on BRCA1 status. Gene expression analysis in the Orien/cBioPortal database revealed an association between LY6E and genes involved in DNA repair, such as Rad21 and PUF60, emphasizing the interplay between DNA repair pathways and immune modulation. Moreover, PUF60, Rad21, and LY6E are located on chromosome 8q24, a locus often amplified and associated with the progression of ovarian cancer. Overall, our study provides novel insights into the molecular determinants of PARPi resistance and highlights LY6E as a promising prognostic biomarker in the management of HRD ovarian cancer. Future studies are needed to fully elucidate the molecular mechanisms underlying the role of LY6E in PARPi resistance.

Semicircles and circular sectors are both ubiquitous in the natural realm. However, mathematically speaking they have represented an enigma since antiquity. In recent years, the author has worked in integral equations with sections of spheres as related to radiative heat transfer and their associated form factors, to the point of defining new postulates. The main theorems thus far enunciated refer to the radiative exchange between circles and half disks, but recently the possibility to treat circular sectors has arrived, thanks to the research already conducted. As is known, to find the exact expression of the configuration factor by integration is complex. In the above mentioned problem of the circular sectors, the author reached the first two steps of the basic formulation for radiant exchange. Subsequently, the novelty of the procedure lies in introducing a finite differences approach for the third and fourth integrals which still remain unsolved, once we have been able to find the preliminary integrals. This possibility had not been identified by former research and the output provides us with an ample variety of unexpected scenarios. As a consequence, we are able to analyze with more precision the spatial transference of radiant heat for figures composed of circular sectors. We already know that spherical shapes cannot be discretized with any accuracy. Therefore, we would be able to reduce a considerable amount of hindrance in the progress of thermal radiation science. Important sequels will be derived for radiation in the entrance to tunnels, aircraft design and lighting as well.

OBJECTIVES:. Acute kidney injury requiring dialysis (AKI-D) commonly occurs in the setting of multiple organ dysfunction syndrome (MODS). Continuous renal replacement therapy (CRRT) is the modality of choice for AKI-D. Mid-term outcomes of pediatric AKI-D supported with CRRT are unknown. We aimed to describe the pattern and impact of organ dysfunction on renal outcomes in critically ill children and young adults with AKI-D. DESIGN:. Retrospective cohort. SETTING:. Two large quarternary care pediatric hospitals. PATIENTS:. Patients 26 y old or younger who received CRRT from 2014 to 2020, excluding patients with chronic kidney disease. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Organ dysfunction was assessed using the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) score. MODS was defined as greater than or equal to two organ dysfunctions. The primary outcome was major adverse kidney events at 30 days (MAKE30) (decrease in estimated glomerular filtration rate greater than or equal to 25% from baseline, need for renal replacement therapy, and death). Three hundred seventy-three patients, 50% female, with a median age of 84 mo (interquartile range [IQR] 16–172) were analyzed. PELOD-2 increased from 6 (IQR 3–9) to 9 (IQR 7–12) between ICU admission and CRRT initiation. Ninety-seven percent of patients developed MODS at CRRT start and 266 patients (71%) had MAKE30. Acute kidney injury (adjusted odds ratio [aOR] 3.55 [IQR 2.13–5.90]), neurologic (aOR 2.07 [IQR 1.15–3.74]), hematologic/oncologic dysfunction (aOR 2.27 [IQR 1.32–3.91]) at CRRT start, and progressive MODS (aOR 1.11 [IQR 1.03–1.19]) were independently associated with MAKE30. CONCLUSIONS:. Ninety percent of critically ill children and young adults with AKI-D develop MODS by the start of CRRT. Lack of renal recovery is associated with specific extrarenal organ dysfunction and progressive multiple organ dysfunction. Currently available extrarenal organ support strategies, such as therapeutic plasma exchange lung-protective ventilation, and other modifiable risk factors, should be incorporated into clinical trial design when investigating renal recovery.

PurposeTo characterize the effect of sampling window size on maps of foveal cone density derived from adaptive optics scanning light ophthalmoscope (AOSLO) images of the cone mosaic.MethodsForty-four AOSLO-derived montages of the foveal cone mosaic (300 x 300µm) were used for this study (from 44 individuals with normal vision). Cone photoreceptor coordinates were semi-automatically identified by one experienced grader. From these coordinates, cone density matrices across each foveal montage were derived using 10 different sampling window sizes containing 5, 10, 15, 20, 40, 60, 80, 100, 150, or 200 cones. For all 440 density matrices, we extracted the location and value of peak cone density (PCD), the cone density centroid (CDC) location, and cone density at the CDC.ResultsAcross all window sizes, PCD values were larger than those extracted at the CDC location, though the difference between these density values decreased as the sampling window size increased (p

Purpose: To evaluate and compare the effectiveness of nearest neighbor (NN)- and variational autoencoder (VAE)-smoothing algorithms to reduce variability and enhance the performance of glaucoma visual field (VF) progression models. Design: Longitudinal cohort study. Subjects: 7150 eyes (4232 patients), with ≥ 5 years of follow-up and ≥ 6 visits. Methods: Vsual field thresholds were smoothed with the NN and VAE algorithms. The mean total deviation (mTD) and VF index rates, pointwise linear regression (PLR), permutation of PLR (PoPLR), and the glaucoma rate index were applied to the unsmoothed and smoothed data. Main Outcome Measures: The proportion of progressing eyes and the conversion to progression were compared between the smoothed and unsmoothed data. A simulation series of noiseless VFs with various patterns of glaucoma damage was used to evaluate the specificity of the smoothing models. Results: The mean values of age and follow-up time were 62.8 (standard deviation: 12.6) years and 10.4 (standard deviation: 4.7) years, respectively. The proportion of progression was significantly higher for the NN and VAE smoothed data compared with the unsmoothed data. VF progression occurred significantly earlier with both smoothed data compared with unsmoothed data based on mTD rates, PLR, and PoPLR methods. The ability to detect the progressing eyes was similar for the unsmoothed and smoothed data in the simulation data. Conclusions: Smoothing VF data with NN and VAE algorithms improves the signal-to-noise ratio for detection of change, results in earlier detection of VF progression, and could help monitor glaucoma progression more effectively in the clinical setting. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Purpose: To evaluate the thickness of the macular retina and central choroid in an indigenous population from Ghana, Africa and to compare them with those measured among individuals with European or African ancestry. Design: Cross-sectional study, systematic review, and meta-analyses. Participants: Forty-two healthy Ghanaians, 37 healthy individuals with European ancestry, and an additional 1427 healthy subjects with African ancestry from previously published studies. Methods: Macular retinal thickness in the fovea, parafovea, and perifovea and central choroidal thickness were extracted from OCT volume scans. Associations with ethnicity, age, and sex were assessed using mixed-effect regression models. Monte Carlo simulations were performed to determine the sensitivity of significant associations to additional potential confounders. Pooled estimates of retinal thickness among other groups with African ancestry were generated through systematic review and meta-analyses. Main Outcome Measures: Macular retinal thickness and central choroidal thickness and their association with ethnicity, age, and sex. Results: When adjusted for age and sex, the macular retina and central choroid of Ghanaians are significantly thinner as compared with subjects with European ancestry (P < 0.001). A reduction in retinal and choroidal thickness is observed with age, although this effect is independent of ethnicity. Meta-analyses indicate that retinal thickness among Ghanaians differs markedly from that of African Americans and other previously reported indigenous African populations. Conclusions: The thickness of the retina among Ghanaians differs not only from those measured among individuals with European ancestry, but also from those obtained from African Americans. Normative retinal and choroidal parameters determined among individuals with African or European ancestry may not be sufficient to describe indigenous African populations. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract Most patients with advanced ovarian cancer (OC) relapse and progress despite systemic therapy, pointing to the need for improved and tailored therapy options. Functional precision medicine can help to identify effective therapies for individual patients in a clinically relevant timeframe. Here, we present a scalable functional precision medicine platform: DET3Ct (Drug Efficacy Testing in 3D Cultures), where the response of patient cells to drugs and drug combinations are quantified with live-cell imaging. We demonstrate the delivery of individual drug sensitivity profiles in 20 samples from 16 patients with ovarian cancer in both 2D and 3D culture formats, achieving over 90% success rate in providing results six days after operation. In this cohort all patients received carboplatin. The carboplatin sensitivity scores were significantly different for patients with a progression free interval (PFI) less than or equal to 12 months and those with more than 12 months (p

Protein variation that occurs during alternative splicing has been shown to play a major role in disease onset and oncogenesis. Due to this, we have developed OutSplice, a user-friendly algorithm to classify splicing outliers in tumor samples compared to a distribution of normal samples. Several tools have previously been developed to help uncover splicing events, each coming with varying methodologies, complexities, and features that can make it difficult for a new researcher to use or to determine which tool they should be using. Therefore, we benchmarked several algorithms to determine which may be best for a particular user’s needs and demonstrate how OutSplice differs from these methodologies. We find that despite detecting a lower number of genes with significant aberrant events, OutSplice is able to identify those that are biologically impactful. Additionally, we identify 17 genes that contain significant splicing alterations in tumor tissue that were discovered across at least 5 of the tested algorithms, making them good candidates for future studies. Overall, researchers should consider a combined use of OutSplice with other splicing software to help provide additional validation for aberrant splicing events and to narrow down biologically relevant events.

Lymphocytic choriomeningitis virus is an underreported cause of miscarriage and neurologic disease. Surveillance remains challenging because of nonspecific symptomatology, inconsistent case reporting, and difficulties with diagnostic testing. We describe a case of acute lymphocytic choriomeningitis virus disease in a person living with HIV in Connecticut, USA, identified by using quantitative reverse transcription PCR.

Moringa oleifera (M. oleifera) is a plant widely used for its beneficial properties both in medical and non-medical fields. Because they produce bioactive metabolites, plants are a major resource for drug discovery. In this study, two different cultivars of leaves of M. oleifera (Salento and Barletta) were obtained by maceration or microwave-assisted extraction (MAE). We demonstrated that extracts obtained by MAE exhibited a lower cytotoxic profile compared to those obtained by maceration at concentrations ranged from 25 to 400 µg/mL, on both Vero CCL-81 and Vero/SLAM cells. We examined their antiviral properties against two viruses, i.e., the human coronavirus 229E (HCoV-229E) and measles virus (MeV), which are both responsible for respiratory infections. The extracts were able to inhibit the infection of both viruses and strongly prevented their attack and entry into the cells in a range of concentrations from 50 to 12 µg/mL. Particularly active was the variety of Salento that registered a 50% inhibitory concentration (IC50) at 21 µg/mL for HCoV-229E and at 6 µg/mL for MeV. We identified the presence of several compounds through high performance liquid chromatography (HPLC); in particular, chlorogenic and neochlorogenic acids, quercetin 3-O-β-d-glucopyranoside (QGP), and glucomoringin (GM) were mainly observed. In the end, M. oleifera can be considered a promising candidate for combating viral infections with a very strong action in the early stages of viral life cycle, probably by destructuring the viral particles blocking the virus–cell fusion.

Most statistical modeling applications involve the consideration of a candidate collection of models based on various sets of explanatory variables. The candidate models may also differ in terms of the structural formulations for the systematic component and the posited probability distributions for the random component. A common practice is to use an information criterion to select a model from the collection that provides an optimal balance between fidelity to the data and parsimony. The analyst then typically proceeds as if the chosen model was the only model ever considered. However, such a practice fails to account for the variability inherent in the model selection process, which can lead to inappropriate inferential results and conclusions. In recent years, inferential methods have been proposed for multimodel frameworks that attempt to provide an appropriate accounting of modeling uncertainty. In the frequentist paradigm, such methods should ideally involve model selection probabilities, i.e., the relative frequencies of selection for each candidate model based on repeated sampling. Model selection probabilities can be conveniently approximated through bootstrapping. When the Akaike information criterion is employed, Akaike weights are also commonly used as a surrogate for selection probabilities. In this work, we show that the conventional bootstrap approach for approximating model selection probabilities is impacted by bias. We propose a simple correction to adjust for this bias. We also argue that Akaike weights do not provide adequate approximations for selection probabilities, although they do provide a crude gauge of model plausibility.

Glyptostrobus pensilis (Staunton ex D. Don) K. Koch is a critically endangered species, native to southeastern China and also very locally found in Dak Lak Province, Vietnam. Essential oil isolated from leaves is a monoterpene-rich oil containing mainly limonene (33.3%), α-pinene (23.4%) and bornyl acetate (9.2%). The composition of G. pensilis wood oil is rather complex and the identification of individual components needed fractionation over column chromatography. The main components, identified by GC(RI), GC-MS and 13C NMR, were cedrol (29.3%), occidentalol (6.6%) and occidentalol isomer (5.9%).

Although car ownership continues to rise worldwide, temporary or more lasting phases of demotorization (reduction in the number of vehicles owned) are taking place at the household level. Existing studies show that the probability of demotorization increases at certain stages of the life cycle, for example, associated with a reduction in household size or income, or a move to a neighborhood with better transit provision. However, the rationale and temporalities of the decision-making processes involved remain obscure. This knowledge could be useful in informing public action on the measures needed in different categories of territories and populations to encourage a steady and sustainable fall in car ownership. As its contribution to these questions, this article focuses on the influence of spatial factors on household demotorization. The methodology draws on 51 interviews conducted in 2018 with demotorized households in four French urban areas (Paris, Lyon, Bordeaux, and Dijon). The findings highlight the role of the characteristics of the current place of residence, changes in the place of residence or place of work, and the spatial dimensions of travel socialization. If, as things stand, permanent and voluntary relinquishment of the car is only possible in very dense urban areas, our results show firstly that there is a strong case for working on mobility representations and practices from a very early age and, secondly, the importance of implementing planning policies and alternatives to the private car that are credible in areas of lower population density.

Pulmonary arteriovenous malformations (PAVMs) can be asymptomatic or result in a range of complications such as brain abscesses or cryptogenic emboli, which can contribute to morbidity and mortality if not diagnosed and treated in a timely manner. To date, there have been several reports of delayed diagnosis of PAVMs, which have been largely attributed to the misconception that PAVMs are too rare to be of clinical significance. Furthermore, because intracardiac shunting secondary to a patent foramen ovale (PFO) or atrial septal defect (ASD) also results in a positive saline contrast study with echocardiography, PAVM can be easily misdiagnosed as an intracardiac right-toleft shunt. However, there are unique echocardiographic features that differentiate between intracardiac shunting due to a PFO or ASD and extracardiac shunting such as in PAVM. This case details the course of a patient with recurrent cryptogenic strokes that was initially misattributed to a PFO and was only correctly diagnosed with multiple PAVMs after two failed attempts at PFO closure. This case serves as a reminder of an alternative etiology of right-to-left shunt and its presentation on imaging, which echocardiographers must be familiar with.

Abstract Background Modern computational modeling could provide the key to obtaining new insights into the mechanisms of maize stalk failure as well as suggesting new ways to improve stalk strength. However, a complete set of mechanical properties of maize tissues is required to enable computational modeling of maize stems. This study developed two compression test methods for obtaining the longitudinal modulus of elasticity of both rind and pith tissues, assessed the influence of water content on tissue properties, and investigated the relationship between rind modulus and pith modulus. These methods involved uniform 5–7 cm segments of maize stems which were scanned using a flatbed scanner then tested in compression using a universal testing machine in both intact and dissected (rind-only and pith-only) states. Results The modulus of elasticity of pith tissues was highest for fully turgid specimens and decreased as water was removed from the specimens. Water content was negatively correlated with the modulus of elasticity of the rind. Rind and pith tissues were found to be weakly correlated. The median ratio of rind modulus to pith modulus was found to be 17. Of the two methods investigated, the pith-only specimen preparation was found to be simple reliable while the rind-only method was found to be adversely affected by lateral bowing of the specimen. Conclusions Researchers can use the information in this paper to improve computational models of maize stems in three ways: (1) by incorporating realistic values of the longitudinal modulus of elasticity of pith and rind tissues; (2) by selecting pith and rind properties that match empirically observed ratios; and (3) by incorporating appropriate dependencies between these material properties and water content. From an experimental perspective, the intact/pith-only experimental method outlined in this paper is simpler than previously reported methods and provides reliable estimates of both pith and rind modulus of elasticity values. Further research using this measurement method is recommended to more clearly understand the influence of water content and turgor pressure on tissue properties.

Abstract Polarization dynamics and domain structure evolution in ferroelectric Al0.93B0.07N are studied using piezoresponse force microscopy and spectroscopies in ambient and controlled atmosphere environments. The application of negative unipolar and bipolar first‐order reverse curve (FORC) waveforms leads to a protrusion‐like feature on the Al0.93B0.07N surface and a reduction of electromechanical response due to electrochemical reactivity. A surface change is also observed on the application of fast alternating current bias. At the same time, the application of positive biases does not lead to surface changes. Comparatively in a controlled glove box atmosphere, stable polarization patterns can be observed, with minuscule changes in surface morphology. This surface morphology change is not isolated to applying biases to free surface, a similar topographical change is also observed at the electrode edges when cycling a capacitor in an ambient environment. The study suggests that surface electrochemical reactivity may have a significant impact on the functionality of this material in the ambient environment. However, even in the controlled atmosphere, the participation of the surface ions in polarization switching phenomena and ionic compensation is possible.