An active site mutation induces oxygen reactivity in D-arginine dehydrogenase: A case of superoxide diverting protons.

Enzymes are potent catalysts that increase biochemical reaction rates by several orders of magnitude. Flavoproteins are a class of enzymes whose classification relies on their ability to react with molecular oxygen (O2) during catalysis using ionizable active site residues. Pseudomonas aeruginosa D-arginine dehydrogenase (PaDADH) is a flavoprotein that oxidizes D-arginine for P. aeruginosa survival and biofilm formation. The crystal structure of PaDADH reveals the interaction of the glutamate 246 (E246) side chain with the substrate and at least three other active site residues, establishing a hydrogen bond network in the active site. Additionally, E246 likely ionizes to facilitate substrate binding during PaDADH catalysis. This study aimed to investigate how replacing the E246 residue with leucine affects PaDADH catalysis and its ability to react with O2 using steady-state kinetics coupled with pH profile studies. The data reveal a gain of O2 reactivity in the E246L variant, resulting in a reduced flavin semiquinone species and superoxide (O2•-) during substrate oxidation. The O2•- reacts with active site protons, resulting in an observed nonstoichiometric slope of 1.5 in the enzyme's log (kcat/Km) pH profile with D-arginine. Adding superoxide dismutase results in an observed correction of the slope to 1.0. This study demonstrates how O2•- can alter the slopes of limbs in the pH profiles of flavin-dependent enzymes and serves as a model for correcting nonstoichiometric slopes in elucidating reaction mechanisms of flavoproteins.

Water birth: a systematic review and meta-analysis of maternal and neonatal outcomes.

OBJECTIVE: This systematic review and meta-analysis aimed to conduct a thorough and contemporary assessment of maternal and neonatal outcomes associated with water birth in comparison with land-based birth. DATA SOURCES: We conducted a comprehensive search of PubMed, EMBASE, CINAHL, and gray literature sources, from inception to February 28, 2023. STUDY ELIGIBILITY CRITERIA: We included randomized and nonrandomized studies that assessed maternal and neonatal outcomes in patients who delivered either conventionally or while submerged in water. METHODS: Pooled unadjusted odds ratios with 95% confidence intervals were calculated using a random-effects model (restricted maximum likelihood method). We assessed the 95% prediction intervals to estimate the likely range of future study results. To evaluate the robustness of the results, we calculated fragility indices. Maternal infection was designated as the primary outcome, whereas postpartum hemorrhage, perineal lacerations, obstetrical anal sphincter injury, umbilical cord avulsion, low Apgar scores, neonatal aspiration requiring resuscitation, neonatal infection, neonatal mortality within 30 days of birth, and neonatal intensive care unit admission were considered secondary outcomes. RESULTS: Of the 20,642 articles identified, 52 were included in the meta-analyses. Based on data from observational studies, water birth was not associated with increased probability of maternal infection compared with land birth (10 articles, 113,395 pregnancies; odds ratio, 0.93; 95% confidence interval, 0.76-1.14). Patients undergoing water birth had decreased odds of postpartum hemorrhage (21 articles, 149,732 pregnancies; odds ratio, 0.80; 95% confidence interval, 0.68-0.94). Neonates delivered while submerged in water had increased odds of cord avulsion (10 articles, 91,504 pregnancies; odds ratio, 1.75; 95% confidence interval, 1.38-2.24) and decreased odds of low Apgar scores (21 articles, 165,917 pregnancies; odds ratio, 0.69; 95% confidence interval, 0.58-0.82), neonatal infection (15 articles, 53,635 pregnancies; odds ratio, 0.64; 95% confidence interval, 0.42-0.97), neonatal aspiration requiring resuscitation (19 articles, 181,001 pregnancies; odds ratio, 0.60; 95% confidence interval, 0.43-0.84), and neonatal intensive care unit admission (30 articles, 287,698 pregnancies; odds ratio, 0.56; 95% confidence interval, 0.45-0.70). CONCLUSION: When compared with land birth, water birth does not appear to increase the risk of most maternal and neonatal complications. Like any other delivery method, water birth has its unique considerations and potential risks, which health care providers and expectant parents should evaluate thoroughly. However, with proper precautions in place, water birth can be a reasonable choice for mothers and newborns, in facilities equipped to conduct water births safely.

Zirconium Hydride Catalysis Initiated by Tetrabutylammonium Fluoride.

In our drug discovery campaigns to target the oncogenic drivers of cancers, the demand for a chemoselective, stereoselective and economical synthesis of chiral benzylamines drove the development of a catalytic zirconium hydride reduction. This methodology uses the inexpensive, bench stable zirconocene dichloride, and a novel tetrabutylammonium fluoride activation tactic to catalytically generate a metal hydride under ambient conditions. The diastereo- and chemoselectivity of this reaction was tested with the preparation of key intermediates from our discovery programs and in the scope of sulfinyl ketimines and carbonyls relevant to medicinal chemistry and natural product synthesis. A preliminary mechanistic investigation conducted into the role of tetrabutylammonium fluoride indicates that formation of a zirconocene fluoride occurs to initiate catalysis. The implications of this convenient activation approach may provide expanded roles for zirconium hydrides in catalytic transformations.

Sucralose (C12H19Cl3O8) impact on microbial activity in estuarine and freshwater marsh soils.

As the general population's diet has shifted to reflect current weight-loss trends, there has been an increase in zero-calorie artificial sweetener usage. Sucralose (C12H19Cl3O8), commonly known as Splenda® in the USA, is a primary example of these sweeteners. In recent years, sucralose has been identified as an environmental contaminant that cannot easily be broken down via bacterial decomposition. This study focuses on the impact of sucralose presence on microbial communities in brackish and freshwater systems. Microbial respiration and fluorescence were measured as indicators of microbial activity in sucralose-dosed samples taken from both freshwater and estuarine marsh environments. Results showed a significant difference between microbial concentration and respiration when dosed with varying levels of sucralose. Diatom respiration implied a negative correlation of community abundance with sucralose concentration. The freshwater cyanobacterial respiration increased in the presence of sucralose, implying a positive correlation of community abundance with sucralose concentration. This was in direct contrast to its brackish water counterpart. However, further investigation is necessary to confirm any potential utility of these communities in the breakdown of sucralose in the marsh environment.

Achilles Tendon Injuries in the Pediatric Population.

BACKGROUND: Achilles tendon injuries are common in adults, and there is extensive literature describing the injury characteristics and treatment of these adult injuries. However, Achilles injuries are rare in the pediatric population and as a result, there is limited research reported on this age group. We therefore sought to characterize the injury presentation, treatment and outcomes for pediatric patients with partial and complete Achilles injuries. METHODS: A retrospective chart review was conducted of patients aged 0-18 treated for Achilles tendon injuries at 2 geographically distinct tertiary institutions between 2008 and 2021. Data collected included demographics, injury characteristics, and treatment course. Injury types were separated into 2 cohorts: traumatic Achilles injuries and ruptures due to muscular contraction. Traumatic injuries were further delineated into 2 injury mechanisms: open injuries related to penetrating trauma and closed injuries related to blunt trauma. Standard descriptive analyses were utilized to summarize findings. RESULTS: Thirty-nine patients (43.6% female, median age 15 years) were identified, 29 (74.4%) of whom had complete tears. Twenty-five patients (64.1%) presented with traumatic injuries; among these, 48.0% (n=12/25) were ≤12 years. All patients ≤12 years sustained a traumatic injury. The most common traumatic mechanism was an open laceration due to penetrating trauma (68.0%), followed by closed ruptures associated with blunt trauma (32.0%). Fourteen patients (35.9%) presented with closed ruptures due to muscular contraction. Four patients (10.2%) had a prior history of clubfoot treated with Achilles tenotomy. Thirty-five patients (89.7%) were surgically treated with an open repair. The median immobilization period across all patients was 11 weeks (interquartile range: 10-12), starting most commonly with a posterior splint (46.2%) and concluding with a CAM boot (94.9%). Of patients with full follow-up data (n=22/39), all resumed normal activities, with a median clearance time of 6 months (interquartile range: 5-7.9). CONCLUSIONS: We found that older adolescents (≥14 y) were more likely to rupture their Achilles tendon through a forceful muscular contraction, whereas younger patients (≤12 y) were more likely to injure their Achilles via a traumatic mechanism. Most patients were treated operatively and returned to sports at a median time of 6 months. A further prospective study is warranted to better characterize treatment protocols and patient outcomes in this population. LEVEL OF EVIDENCE: Level-IV.

Percutaneous approach to left ventricular assist device decommissioning.

OBJECTIVE: To assess the outcomes of a single-center experience with percutaneous left ventricular assist device (LVAD) decommissioning. BACKGROUND: Patients with LVADs may eventually require their removal, either due to recovery of left ventricular function or recurrent complications. Traditionally, withdrawal of LVAD support has been managed with surgical device explantation, which carries significant procedural risks. Transcatheter LVAD decommissioning, with outflow graft occlusion and driveline transection, has recently been described as an alternative to surgical removal. METHODS: Here, we report on a retrospective cohort of five consecutive cases treated with transcatheter LVAD decommissioning. RESULTS: The procedure was effective in all cases, and no patient experienced procedure-related complications. At midterm follow-up, the three patients who had myocardial function recovery were alive and had not experienced heart failure-related symptoms or complications. CONCLUSION: Percutaneous LVAD decommissioning appears to be a safe and effective approach to LVAD treatment discontinuation.

On the Relationship Between Oceanic Plate Speed, Tectonic Stress, and Seismic Anisotropy.

Seismic radial anisotropy (the squared ratio between the speeds of horizontally and vertically polarized shear waves, ξ = V S H 2 V S V 2 ) is a powerful tool to probe the direction of mantle flow and accumulated strain. While previous studies have confirmed the dependence of azimuthal anisotropy on plate speed, the first order control on radial anisotropy is unclear. In this study, we develop 2D ridge flow models combined with mantle fabric calculations to report that faster plates generate higher tectonics stresses and strain rates which lower the dislocation creep viscosity and lead to deeper anisotropy than beneath slower plates. We apply the SGLOBE-rani tomographic filter, resulting in a flat depth-age trend and stronger anisotropy beneath faster plates, which correlates well with 3D global anisotropic mantle models. Our predictions and observations suggest that as plate speed increases from 2 to 8 cm/yr, radial anisotropy increases by ∼0.01-0.025 in the upper 100-200 km of the mantle between 10 and 60 Ma.

Nr2f-dependent allocation of ventricular cardiomyocyte and pharyngeal muscle progenitors.

Multiple syndromes share congenital heart and craniofacial muscle defects, indicating there is an intimate relationship between the adjacent cardiac and pharyngeal muscle (PM) progenitor fields. However, mechanisms that direct antagonistic lineage decisions of the cardiac and PM progenitors within the anterior mesoderm of vertebrates are not understood. Here, we identify that retinoic acid (RA) signaling directly promotes the expression of the transcription factor Nr2f1a within the anterior lateral plate mesoderm. Using zebrafish nr2f1a and nr2f2 mutants, we find that Nr2f1a and Nr2f2 have redundant requirements restricting ventricular cardiomyocyte (CM) number and promoting development of the posterior PMs. Cre-mediated genetic lineage tracing in nr2f1a; nr2f2 double mutants reveals that tcf21+ progenitor cells, which can give rise to ventricular CMs and PM, more frequently become ventricular CMs potentially at the expense of posterior PMs in nr2f1a; nr2f2 mutants. Our studies reveal insights into the molecular etiology that may underlie developmental syndromes that share heart, neck and facial defects as well as the phenotypic variability of congenital heart defects associated with NR2F mutations in humans.

Younger Patients Are More Likely to Undergo Arthroscopic Meniscal Repair and Revision Meniscal Surgery in a Large Cross-Sectional Cohort.

PURPOSE: To evaluate recent trends in the treatment of meniscal tears with arthroscopic repair and debridement and to assess revision surgery within 2 years using a large cross-sectional database. METHODS: Patients with a diagnosis of meniscal tear from 2010 to 2017 were queried using the Mariner data set from PearlDiver. Patient demographic data were analyzed and tracked via International Classification of Diseases, Tenth Revision codes to investigate subsequent ipsilateral meniscal procedures and conversion to total knee arthroplasty within 2 years after index meniscal surgery. RESULTS: Of the 1,383,161 patients with a diagnosis of meniscal tear, 53.0% underwent surgical treatment. Surgical treatment consisted of meniscal debridement in 96.6% of patients and meniscal repair in 3.4%. The percentage of meniscal repairs increased from 2.7% to 4.4% over the 8-year period evaluated, whereas the percentage of meniscal debridement decreased from 97.3% to 95.6% (P < .0001). Younger patients were more likely to undergo meniscal repair (23% of those aged 10-19 years) than older patients (<1% of those aged ≥60 years). Among the 191,729 patients with International Classification of Diseases, Tenth Revision coding and 2-year follow-up, 10.6% of patients with index meniscal repair required a revision meniscal operation and 1.2% underwent conversion to arthroplasty. Subsequent meniscal procedures within 2 years after index meniscal repair included meniscal debridement in 81.6% of patients and revision repair in 18.4%. Patients who initially underwent meniscal debridement were less likely to undergo revision meniscal surgery (5.1%), but 4.7% required conversion to arthroplasty. Patients aged 10 to 19 years were most likely to undergo revision meniscal procedures after both index meniscal repair (12.8%) and meniscal debridement (8.8%). CONCLUSIONS: The rate of meniscal repair is increasing over time, with patients younger than 30 years most likely to undergo repair for a meniscal tear. Revision surgery for meniscal repair or debridement is more common in adolescents and patients who undergo an index meniscal repair. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Excitation function of 54Fe(p,α)51Mn from 9.5 MeV to 18 MeV.

Excitation function of the 54Fe(p,α)51Mn reaction was measured from 9.5 to 18 MeV E 0 , p + by activating a foil stack of 54Fe electrodeposited on copper substrates. Residual radionuclides were quantified by HPGe gamma ray spectrometry. Both 51Mn (t 1/2 = 46.2 min, 〈 E ß + 〉 = 963.7 keV , I ß + = 97 % ; E γ = 749.1 keV, I γ = 0.265%) and its radioactive daughter, 51Cr (t 1/2 = 27.704d, E γ = 320.1 keV, I γ = 9.91%), were used to indirectly quantify formation of 51Mn. Results agree within uncertainty to the only other measurement in literature and predictions of default TALYS theoretical code. Final relative uncertainties are within ±12%.

Hepatocyte HIF-1 and Intermittent Hypoxia Independently Impact Liver Fibrosis in Murine Nonalcoholic Fatty Liver Disease.

Obstructive sleep apnea is associated with insulin resistance, lipid dysregulation, and hepatic steatosis and fibrosis in nonalcoholic fatty liver disease (NAFLD). We have previously shown that hepatocyte HIF-1 (hypoxia-inducible factor-1) mediates the development of liver fibrosis in a mouse model of NAFLD. We hypothesized that intermittent hypoxia (IH) modeling obstructive sleep apnea would worsen hepatic steatosis and fibrosis in murine NAFLD, via HIF-1. Mice with hepatocyte-specific deletion of Hif1a (Hif1a-/-hep) and wild-type (Hif1aF/F) controls were fed a high trans-fat diet to induce NAFLD with steatohepatitis. Half from each group were exposed to IH, and the other half were exposed to intermittent air. A glucose tolerance test was performed just prior to the end of the experiment. Mitochondrial efficiency was assessed in fresh liver tissue at the time of death. The hepatic malondialdehyde concentration and proinflammatory cytokine levels were assessed, and genes of collagen and fatty acid metabolism were examined. Hif1a-/-hep mice gained less weight than wild-type Hif1a mice (-2.3 g, P = 0.029). There was also a genotype-independent effect of IH on body weight, with less weight gain in mice exposed to IH (P = 0.003). Fasting glucose, homeostatic model assessment for insulin resistance, and glucose tolerance test results were all improved in Hif1a-/-hep mice. Liver collagen was increased in mice exposed to IH (P = 0.033) and was reduced in Hif1a-/-hep mice (P < 0.001), without any significant exposure/genotype interaction being demonstrated. Liver TNF-α and IL-1ß were significantly increased in mice exposed to IH and were decreased in Hif1a-/-hep mice. We conclude that HIF-1 signaling worsens the metabolic profile and hastens NAFLD progression and that IH may worsen liver fibrosis. These effects are plausibly mediated by hepatic inflammatory stress.

An interventional approach to left ventricular assist device outflow graft obstruction.

BACKGROUND: LVADs provide life-sustaining treatment for patients with heart failure, but their complexity allows for complications. One complication, LVAD outflow graft obstruction, may be misdiagnosed as intraluminal thrombus, when more often it is extraluminal compression from biodebris accumulation. It can often be treated endovascularly with stenting. This case series describes diagnostic and procedural techniques for the treatment of left ventricular assist device (LVAD) outflow graft obstruction. METHODS: We present four patients with LVADs who developed LVAD outflow graft obstruction within the bend relief-covered segment. All were initially diagnosed with computed tomographic angiography (CTA). All underwent invasive evaluation with intravascular ultrasound (IVUS), then were treated with stenting. After misdiagnosing a twist, we developed the technique of balloon "graftoplasty" to ensure suitability for stent delivery in subsequent cases. RESULTS: All patients presented with low-flow alarms and symptoms of low output, and were diagnosed with outflow graft obstruction by CTA. In all four, IVUS confirmed an extraluminal etiology. Patient 1 was treated with stenting and had a good outcome. Patient 2's obstruction was from twisting, rather than biodebris accumulation, and had sub-optimal stent expansion and ultimately required surgery. Balloon "graftoplasty" was used in subsequent cases to ensure subsequent stent expansion. Patients 3 and 4 were successfully stented. All improved after treatment. CONCLUSIONS: In patients with LVAD outflow graft obstruction, IVUS can distinguish intraluminal thrombus from extraluminal compression. Balloon "graftoplasty" can ensure that the outflow graft will respond to stenting. Many cases of LVAD outflow graft obstruction should be amenable to endovascular treatment.

Anatomical and physiological variation of the hyoid musculature during swallowing in infant pigs.

The function of a muscle is impacted by its line of action, activity timing and contractile characteristics when active, all of which have the potential to vary within a behavior. One function of the hyoid musculature is to move the hyoid bone during swallowing, yet we have little insight into how their lines of action and contractile characteristics might change during a swallow. We used an infant pig model to quantify the contractile characteristics of four hyoid muscles during a swallow using synchronized electromyography, fluoromicrometry and high-speed biplanar videofluoroscopy. We also estimated muscle line of action during a swallow using contrast-enhanced CT-scanned muscles animated to move with the hyoid bone and found that as the hyoid elevated, the line of action of the muscles attached to it became greater in depression. We also found that muscles acted eccentrically and concentrically, which was correlated with hyoid movement. This work contributes to our understanding of how the musculature powering feeding functions during swallowing.

Age of acquisition effects in recognition without identification tasks.

The Age of Acquisition (AoA) effect results in early-acquired words being processed more quickly and accurately than later-acquired words. This effect is argued to result from a gradual development of semantic representations and a changing neural network throughout development (Chang, Y.-N., Monaghan, P., & Welbourne, S., 2019). Some forms of the Recognition Without Identification (RWI) effects have been observed at a perceptual level. The present study used the RWI paradigm to examine whether the AoA effect is located at the perceptual loci. A total of 174 participants were presented a list of pictures (Experiment 1) or words (Experiment 2) followed by a list of mixed early- and late-acquired picture or word fragments that participants had to identify; half of which corresponded to studied words and half of which to unstudied words. Irrespective of whether the item was identified, participants then rated the likelihood that the item appeared in the study phase. In both experiments, results showed that studied items were recognised more accurately than unstudied items, even when they could not be identified and late-acquired items were recognised more than early-acquired items, even when they were not identified. Finally, RWI interacted with the AoA effect only in pictorial stimuli, suggesting that the RWI and AoA effects are located at the perceptual level.

Comparison of the accuracy of telehealth examination versus clinical examination in the detection of shoulder pathology.

HYPOTHESIS/BACKGROUND: In 2017, the American Orthopaedic Association advocated for the increased use of telehealth as an assessment and treatment platform, and demand has significantly increased during the coronavirus disease 2019 pandemic. Diagnostic effectiveness (also called overall diagnostic accuracy) and reliability of a telehealth clinical examination vs. a traditional shoulder clinical examination (SCE) has not been established. Our objective is to compare the diagnostic effectiveness of a telehealth shoulder examination against an SCE for rotator cuff tear (RCT), using magnetic resonance imaging (MRI) as a reference standard; secondary objectives included assessing agreement between test platforms and validity of individualized tests. We hypothesize that tests provided in a telehealth platform would not have inferior diagnostic effectiveness to an SCE. METHODS: The study is a case-based, case-control design. Two clinicians selected movement, strength, and special tests for the SCE that are associated with the diagnosis of RCT and identified similar tests to replicate for a simulated telehealth-based examination (STE). Consecutive patients with no prior shoulder surgery or advanced imaging underwent both the SCE and STE in the same visit using 2 separate assessors. We randomized the order of the SCE or STE. A blinded reader assessed an MRI, to be used as a reference standard. We calculated diagnostic effectiveness, which provides values from 0% to 100% as well as agreement statistics (Kappa) between tests by an assessment platform, and sensitivity, specificity, and likelihood ratios for individual tests in both SCE and STE. We compared the diagnostic effectiveness (overall) of the SCE and STE with a Mann-Whitney U test. RESULTS: We included 62 consecutive patients with shoulder pain, aged 40 or older; 50 (81%) received an MRI as a reference standard. The diagnostic effectiveness of stand-alone tests was poor regardless of the group, with the exception of a few tests with high specificity. None had greater than 70% accuracy. There was no significant difference between the overall diagnostic effectiveness of the STE and SCE (P = .98). Overall agreement between the STE tests and the SCE tests ranged from poor to moderate (Kappa, 0.07-0.87). CONCLUSION: This study identified initial feasibility and noninferiority of the physician-guided, patient-performed STE when compared with an SCE in the detection of RCTs. Although these results are promising, larger studies are needed for further validation of an STE assessment platform.

Assessing the Appeal of Instagram Electronic Cigarette Refill Liquid Promotions and Warnings Among Young Adults: Mixed Methods Focus Group Study.

BACKGROUND: While marketing for electronic cigarette refill liquids (e-liquids) is widespread on Instagram, little is known about the post elements that create appeal among young adult Instagram users. Further information is needed to help shape regulatory strategies appropriate for social media. OBJECTIVE: This study examined young adult Instagram user perceptions of actual e-liquid marketing posts and US Food and Drug Administration (FDA)-mandated nicotine addiction warning statements on Instagram. METHODS: A series of 12 focus groups (n=69) were held with non-tobacco users, vapers, smokers, and dual users in Wisconsin between September and December 2018. Participants discussed the elements of posts that they found appealing or unappealing, in addition to completing a survey about each post and e-liquid. Focus group transcripts were analyzed by smoking status using a framework analysis approach. RESULTS: Although willingness to try e-liquids was highest among nicotine users, focus group discussions indicated that Instagram posts promoting e-liquids held appeal for individuals across smoking statuses. The primary elements that created appeal were the perceived trustworthiness of the Instagram account, attractive design and flavor visuals, and promotion of flavors and nicotine levels that met personal preferences. Post appeal was reduced by references to vaping subcultures, indicators that the post creator did not take nicotine addiction seriously, and FDA-mandated nicotine warning statements. Non-tobacco users were particularly drawn to posts featuring nicotine-free e-liquids with attractive visual designs and flavors known from foods. CONCLUSIONS: Young adults consider a broad range of elements in assessing the appeal of e-liquid marketing on Instagram, with minor but notable distinctions by smoking status. Non-tobacco users are uniquely drawn to nicotine-free e-liquids and are more deterred by the FDA's mandated nicotine addiction warning statements than those from other smoking statuses. This suggests that it may be possible to tailor policy interventions in a manner that helps to reduce novel uptake of vaping without significantly diminishing its potential harm-reduction benefits.

IL-1/inhibitory κB kinase ε-induced glycolysis augment epithelial effector function and promote allergic airways disease.

BACKGROUND: Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in patients with allergic asthma. OBJECTIVES: We sought to determine whether glycolysis is altered in patients with allergic asthma and to address its importance in the pathogenesis of allergic asthma. METHODS: We examined alterations in glycolysis in sputum samples from asthmatic patients and primary human nasal cells and used murine models of allergic asthma, as well as primary mouse tracheal epithelial cells, to evaluate the relevance of glycolysis. RESULTS: In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1-dependent manner. Furthermore, administration of IL-1ß into the airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A occurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1ß or IL-1α resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1ß- or IL-1α-mediated proinflammatory responses and the stimulatory effects of IL-1ß on house dust mite (HDM)-induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of κB kinase ε was downstream of HDM or IL-1ß and required for HDM-induced glycolysis and pathogenesis of allergic airways disease. Small interfering RNA ablation of lactate dehydrogenase A attenuated HDM-induced increases in lactate levels and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatic patients intrinsically produced more lactate compared with cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatic patients, notably those with greater than 61% neutrophils. A positive correlation was observed between sputum lactate and IL-1ß levels, and lactate content correlated negatively with lung function. CONCLUSIONS: Collectively, these findings demonstrate that IL-1ß/inhibitory κB kinase ε signaling plays an important role in HDM-induced glycolysis and pathogenesis of allergic airways disease.

Early to Midterm Clinical and Radiographic Survivorship of the All-Polyethylene Versus Modular Metal-Backed Tibia Component in Primary Total Knee Replacement.

The purpose of this study was to compare the all-polyethylene tibial component with the modular metal-backed component in primary total knee arthroplasty. A retrospective review of 1064 patients recorded clinical failure, as determined by need for revision surgery, range of motion, and impending radiographic loosening, as evaluated by the presence of radiolucent lines. Mean follow-up was 1.2 and 3 years, respectively. Survival in the all-polyethylene group was 100%, with 95.5% (95% CI: 85.8-98.6) survival in the metal-backed component group at 4.3 years. Thin (<4 mm) radiolucent lines were present in one patient (0.7%) with an all-polyethylene implant and 24 (16.9%) patients with the metalbacked component (p < .001), while one (0.7%) and two (1.4%) patients had evidence of osteolysis, respectively (p = .621). While there were fewer radiolucent lines noted around the all-polyethylene implant on radiographs, the clinical implications of the finding are unknown. In this study population, the all-polyethylene tibial component appears appropriate. (Journal of Surgical Orthopaedic Advances 28(2):108-114, 2019).

Flow-through microfluidic immunosensors with refractive index-matched silica monoliths as volumetric optical detection elements.

A sensitive and rapid absorbance based immunosensor that utilizes ex situ functionalized porous silica monoliths as volumetric optical detection elements is demonstrated in this study. The porous monolith structure facilitates high capture probe density and short diffusion length scales, enabling sensitive and rapid assays. Silica monoliths, synthesized and functionalized with immunocapture probes off-chip before integration into a sealed thermoplastic microfluidic device, serve to capture target antigens during perfusion through the porous structure. Gold nanoparticle immunoconjugates are combined with silver enhancement to create microscale silver clusters, followed by perfusion of an aqueous sucrose solution to limit light scattering and enhance optical signal. Using this approach, detection limits as low as 1 ng/mL are achieved for a sandwich assay, with a dynamic range of at least 4 logs. The results confirm that the combination of on-chip index matching with functionalized porous silica monoliths can enables simple and practical flow-through immunoassays for the sensitive and rapid detection of target antigens.

Case Series: Overnight Wear of Scleral Lens for Persistent Epithelial Defects.

SIGNIFICANCE: This case series demonstrates successful use of PROSE (Prosthetic Replacement of the Ocular Surface Ecosystem) for overnight wear among patients with persistent epithelial defects, while exploring the efficacy of using PROSE reservoir for autologous hematopoietic products during treatment. PURPOSE: This case series proposes a strategic approach to the treatment of refractory cases of persistent epithelial defect via overnight PROSE device wear. CASE REPORTS: We followed three patients with persistent epithelial defect treated with PROSE devices and observed expedited defect resolution and improvement in best-corrected visual acuity over the course of 2 to 4 weeks. In addition to moxifloxacin and preservative-free saline, autologous hematopoietic products were added to the reservoir of two patient's PROSE devices. Patients were advised to wear their PROSE device at all times except for lens cleaning and replacement of reservoir contents every 12 hours. CONCLUSIONS: Together, these cases demonstrated the safety and efficacy of overnight wear of PROSE devices in the treatment of refractory persistent epithelial defect (PED).