Early Time Frame Research Articles

Gelatin methacryloyl biomaterials and strategies for trophoblast research

Rising maternal mortality rates in the U.S. are a significant public health issue that must be addressed; however, much of the basic science information required to target pregnancy-related pathologies have not yet been defined. Placental and blastocyst implantation research are challenging to perform in humans because of the early time frame of these processes in pregnancy and limited access to first trimester tissues. As a result, there is a critical need to develop model systems capable of studying these processes in increasing mechanistic detail. With the recent passing of the FDA Modernization Act 2.0 and advances in tissue engineering methods, three-dimensional microphysiological model systems offer an exciting opportunity to model early stages of placentation. Here, we detail the synthesis, characterization, and application of gelatin methacryloyl (GelMA) hydrogel platforms for studying trophoblast behavior in three-dimensional hydrogel systems. Photopolymerization strategies to fabricate GelMA hydrogels render the hydrogels homogeneous in terms of structure and stable under physiological temperatures, allowing for rigorous fabrication of reproducible hydrogel variants. Unlike other natural polymers that have minimal opportunity to tune their properties, GelMA hydrogel properties can be tuned across many axes of variation, including polymer degree of functionalization, gelatin bloom strength, light exposure time and intensity, polymer weight percent, photoinitiator concentration, and physical geometry. In this work, we aim to inspire and instruct the field to utilize GelMA biomaterial strategies for future placental research. With enhanced microphysiological models of pregnancy, we can now generate the basic science information required to address problems in pregnancy.

Early Cretaceous A-Type Acidic Magmatic Belt in Northern Lhasa Block: Implications for the Evolution of the Bangong–Nujiang Ocean Lithosphere

A-type granites have been the subject of considerable interest due to their distinct anorogenic geological background. The A-type and arc-related granites are crucial in deciphering the evolution of the ocean closure and continental collision in the Tibet Plateau. The demise of the Bangong–Nujiang suture zone (BNSZ) and the Yarlung–Tsangpo suture zone was accompanied by the emplacement of volumes of syn-collisional and post-collisional granites. Controversy has persisted regarding the contribution of the collisional granites within the Lhasa Block to the growth of the Tibetan Plateau. This study provides key evidence about the evolution of the Lhasa Block and Bangong–Nujiang Ocean (BNO) by the newly documented 1200 km long, Early Cretaceous A-type acidic magmatic belt. The resolution was achieved through the utilization of petrology, whole-rock geochemistry, zircon U-Pb geochronology, and in situ zircon Hf isotope analysis of the Burshulaling Granites in the eastern segment and previous existing data in the central and western segment of the Lhasa Block. The Burshulaling Granites are characterized as peraluminous, high-K calc-alkaline series, indicating a post-collision setting with high temperature and low pressure. The zircon grains from two granite samples yield 206Pb/238U ages of 115–113 Ma. In situ zircon Hf analyses with 206Pb/238U ages give εHf(t) of −6.2–0.6, showing prominent characteristics of crust-mantle interaction. Granites from east to west exhibit whole-rock geochemical and geochronological similarities that fall within the well-constrained Early Cretaceous time frame (117–103 Ma) and track post-collisional A-type acidic magmatic belt along BNSZ. We argue that this magmatism resulted from slab break-off or orogenic root detachment, leading to melting and mixing of the lower crust. Meanwhile, this study indicates the existence of the Bangong–Nujiang Ocean southward subduction or a collapse following an Andean-type orogen.

Co-regulatory Proteins Integrate Metabolic Signals to Regulate ESRRG Transcriptional Transactivation in Stomach Parietal Cell Differentiation

Acid-producing stomach parietal cells (PC) are metabolically active and energy demanding cells. Aberrant PC function and census leads to complications ranging from peptic ulcers to stomach adenocarcinoma. Effcient energy expenditure and catabolic metabolism are required for normal PC differentiation from progenitor cells. Here, our data show that the master metabolic transcriptional factor, estrogen-related receptor gamma ( ESRRG), governs murine and human PC differentiation. We are further investigating how known metabolically controlled co-regulatory proteins — Sirtuin 1 (SIRT1), Nuclear Receptor Subfamily 0 Group B Member 2 (NR0B2), and CREB/ATF BZIP Transcription Factor (CREBZF, or SMILE) — integrate stimuli to enable ESRRG transcriptional activation during PC emergence from precursors. Specifically, our lab has developed an acute and reversible PC ablation model to monitor PC recovery in which Simian diphtheria toxin receptor (DTR) expression under the Atp4b promoter targets PC-specific ablation by diphtheria toxin (DT). Additionally, we employ high-dose tamoxifen (HD TAM), which causes a more general gastric injury (independent of tamoxifen effects on estrogen) from PC death along with reactive spasmolytic polypeptide expressing metaplasia (SPEM) of remaining cells. Immunofluorescence, western blotting, and qRT-PCR revealed SIRT1 is upregulated before emergence of early PC clones post-DT and decreases later, suggesting positive regulation of early PC lineage-commitment from stem cells. During the same early time frame, factors NR0B2 and CREBZF decreased, suggesting contrasting roles. Administration of Resv to mice accelerated PC recovery after injury and expanded PCs even at homeostasis. ChIP and ongoing ChIP-seq and Cut&Run assays show ESRRG binds cis-regulatory elements of the metabolic genes and the co-regulatory proteins to promote PC lineage commitment in both mice and in a human gastric cell line in which stable ESRRG-GFP is expressed under a doxycycline-inducible promoter. In other ongoing work, we are generating mice with PC-specific Sirt1/ Nr0b2 ablation to further dissect PC regeneration dynamics and conducting gastric organoid experiments with NR0B2/SIRT1 pharmacological modulators to monitor PC differentiation effects. These organoid samples will be further subjected to epigenetic analysis (Cut&Run, ATACseq) to study chromatin landscape changes. We conclude that cellular metabolic integration by co-regulators enables ESRRG-mediated transactivation during PC differentiation, and SIRT1 promotes early PC lineage-commitment that might offer a promising pro-PC differentiation therapeutic strategy. This work is supported by funding from the NIH through the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

B cells in the pneumococcus-infected lung are heterogeneous and require CD4+ T cell help including CD40L to become resident memory B cells.

Recovery from respiratory pneumococcal infections generates lung-localized protection against heterotypic bacteria, mediated by resident memory lymphocytes. Optimal protection in mice requires re-exposure to pneumococcus within days of initial infection. Serial surface marker phenotyping of B cell populations in a model of pneumococcal heterotypic immunity revealed that bacterial re-exposure stimulates the immediate accumulation of dynamic and heterogeneous populations of B cells in the lung, and is essential for the establishment of lung resident memory B (BRM) cells. The B cells in the early wave were activated, proliferating locally, and associated with both CD4+ T cells and CXCL13. Antagonist- and antibody-mediated interventions were implemented during this early timeframe to demonstrate that lymphocyte recirculation, CD4+ cells, and CD40 ligand (CD40L) signaling were all needed for lung BRM cell establishment, whereas CXCL13 signaling was not. While most prominent as aggregates in the loose connective tissue of bronchovascular bundles, morphometry and live lung imaging analyses showed that lung BRM cells were equally numerous as single cells dispersed throughout the alveolar septae. We propose that CD40L signaling from antigen-stimulated CD4+ T cells in the infected lung is critical to establishment of local BRM cells, which subsequently protect the airways and parenchyma against future potential infections.

Timing of Decompressive Surgery in Patients With Acute Spinal Cord Injury: Systematic Review Update.

Systematic review and meta-analysis. Surgical decompression is a cornerstone in the management of patients with traumatic spinal cord injury (SCI); however, the influence of the timing of surgery on neurological recovery after acute SCI remains controversial. This systematic review aims to summarize current evidence on the effectiveness, safety, and cost-effectiveness of early (≤24hours) or late (>24hours) surgery in patients with acute traumatic SCI for all levels of the spine. Furthermore, this systematic review aims to evaluate the evidence with respect to the impact of ultra-early surgery (earlier than 24hours from injury) on these outcomes. A systematic search of the literature was performed using the MEDLINE database (PubMed), Cochrane database, and EMBASE. Two reviewers independently screened the citations from the search to determine whether an article satisfied predefined inclusion and exclusion criteria. For all key questions, we focused on primary studies with the least potential for bias and those that controlled for baseline neurological status and specified time from injury to surgery. Risk of bias of each article was assessed using standardized tools based on study design. Finally, the overall strength of evidence for the primary outcomes was assessed using the GRADE approach. Data were synthesized both qualitatively and quantitively using meta-analyses. Twenty-one studies met inclusion and exclusion criteria and formed the evidence base for this review update. Seventeen studies compared outcomes between patients treated with early (≤24hours from injury) compared to late (>24hours) surgical decompression. An additional 4 studies evaluated even earlier time frames: <4, <5, <8 or <12hours. Based on moderate evidence, patients were 2times more likely to recover by ≥ 2 grades on the ASIA Impairment Score (AIS) at 6months (RR: 2.76, 95% CI 1.60 to 4.98) and 12months (RR: 1.95, 95% CI 1.26 to 3.18) if they were decompressed within 24hours compared to after 24 hours. Furthermore, moderate evidence suggested that patients receiving early decompression had an additional 4.50 (95% CI 1.70 to 7.29) point improvement on the ASIA motor score. With respect to administrative outcomes, there was low evidence that early decompression may decrease acute hospital length of stay. In terms of safety, there was moderate evidence that suggested the rate of major complications does not differ between patients undergoing early compared to late surgery. Furthermore, there was no difference in rates of mortality, surgical device-related complications, sepsis/systemic infection or neurological deterioration based on timing of surgery. Firm conclusions were not possible with respect to the impact of ultra-early surgery on neurological, functional or safety outcomes given the poor-quality studies, imprecision and the overlap in the time frames examined. This review provides an evidence base to support the update on clinical practice guidelines related to the timing of surgical decompression in acute SCI. Overall, the strength of evidence was moderate that early surgery (≤24hours from injury) compared to late (>24hours) results in clinically meaningful improvements in neurological recovery. Further studies are required to delineate the role of ultra-early surgery in patients with acute SCI.

Gluteal Fat Grafting Technique and Mortality Update Among Surveyed ABCS Surgeons

Background: The demand for gluteal fat grafting (colloquially known as Brazilian butt lift [BBL]) has seen a dramatic increase in the past decade. Brazilian butt lift has been the fastest-growing cosmetic procedure in the United States for several years. During this time, the incidence of pulmonary fat embolisms (PFEs) associated with this procedure has raised safety concerns. Several professional organizations have responded to these concerns with investigational reports to identify the causes and provide recommendations to decrease the mortality associated with this popular cosmetic procedure. Awareness and implementation of these safety recommendations have been a cornerstone to decreasing the mortality rate associated with gluteal fat grafting. Objectives: To provide a comparison of current technical approaches and a mortality update on gluteal fat grafting among surgical members from the American Board of Cosmetic Surgeons (ABCS) within the last 6 years. Also, to determine if specific technical changes in the manner this procedure is performed are improving safety. Methods: An online (emailed) survey regarding perioperative gluteal fat grafting techniques and postoperative outcomes performed by ABCS surgeons within the previous 3 years was collected in 2 different 3-year time frames. Initial data were collected in 2019 for the preceding 3 years 2016-2019. The survey was again repeated in 2022 to collect similar data as before from ABCS member years 2019-2021. The data, which included the total # of BBLs performed, incidence of major infection or fat emboli, cannula size, and injection methods details was compared for each 3-year period. Both sequential studies provided a comparison of the techniques employed as well as morbidity and mortality outcomes. Results: Sixty-four ABCS surgeons who reported performing BBLs responded to the survey in 2019 and reported performing a total of 22 800 (BBLs) gluteal fat grafting cases in a previous 3-year window from 2016 to 2018. More surgeons used a closed system peristaltic pump in the second part of the study as compared to the first (51% vs 22%) ( P &lt; .01). Two cases required in-hospital treatment of infection in the first survey while zero cases were reported for the second survey period ( P = .07). Twenty-five of 64 (39%) reported injecting fat at least into superficial gluteal muscle during this earlier time frame. In this earliest study, there were 3 total cases of PFE reported (2 fatal PFEs and 1 nonfatal PFEs). In 2022, 85 ABCS surgeons who reported performing BBLs responded to the survey. Around 12 172 gluteal fat grafting cases were reported in the second 3-year study from 2019 to 2021 compared to 22 800 in the first study ( P &lt; .01). There was a total of 34 972 BBLs during the entire 6-year study. Most surgeons (82 of the 85) in the second-phase 3-year study reported injecting fat “exclusively” above the muscle ( P &lt; .01). There were no fatal and non-fatal PFEs reported in the follow-up 3-year study in 2022 of ABCS member data from 2019 to 2021 ( P = .03). Conclusions: The mortality report associated with gluteal fat grafting from this survey among surgical members of the ABCS suggests using the current safety recommendations proposed, including injection of fat in the subcutaneous layer only, have led to a decreased risk of PFEs associated with gluteal fat grafting. The mortality rate was zero (0 out of 12 800) when 96% were injecting above muscle only compared to a mortality rate of 1:11 400 (2 of 22 800 cases) when 39% of 22 800 BBLs performed had fat injected into muscle. While there were more BBLs performed during the earlier 3-year study ( P = .07). The mortality rate significantly decreased in the years when only a small minority of cases had fat injected into the muscle. This study adds to other existing literature from professional organizations’ reports on the safety of gluteal fat grafting using the proper safety measure and recommendations.

Enhancement of essential cofactors for in vivo biocatalysis.

A scarcity of cofactors, necessary metabolites or substrates for in vivo enzymatic reactions, is among the major barriers for product synthesis in metabolically engineered cells. This work compares our recently developed cofactor-boosting strategy, which uses xylose reductase (XR) and lactose to increase the intracellular levels of reduced or oxidized nicotinamide adenine dinucleotide (phosphate) (NAD(P)H), adenosine triphosphate (ATP) and acetyl coenzymeA (acetyl-CoA), with other previously reported methods. We demonstrated that the XR/lactose approach enhances levels of sugar alcohols and sugar phosphates, which leads to elevated levels of crucial cofactors required by specific metabolic pathways. The patterns of cofactor enhancement are not uniform and depend upon the specific pathway components that are overexpressed. We term this model the "user-pool" model. Here, we investigated metabolite alteration in the fatty-alcohol-producing system in the presence of XR/lactose within an early time frame (5 min after the bioconversion started). All metabolite data were analyzed using untargeted metabolomics. We found that the XR/lactose system could improve fatty-alcohol production as early as 5 min after the bioconversion started. The enhancement of key cofactors and intermediates, such as hexitol, NAD(P)H, ATP, 3-phosphoglycerate, acetyl-CoA, 6-phosphogluconate (6-PG) and glutathione, was consistent with those previously reported on a longer time scale (after 1 h). However, measurements performed at the early time reported here showed detectable differences in metabolite enhancement patterns, such as those of ATP, NADPH, acetyl-CoA and glutathione. These data could serve as a basis for future analysis of metabolic flux alteration by the XR/lactose system. Comparative analysis of the cofactor enhancement by XR and other methods suggests that XR/lactose can serve as a simple tool to increase levels of various cofactors for microbial cell factories.

Do advances in technology translate to improved outcomes? Comparing robotic bariatric surgery outcomes over two-time intervals utilizing the MBSAQIP database.

This study aims to compare outcomes and utilization of robotics in bariatric procedures across two-time intervals, chosen because they correspond to drastic changes in technology utilization-namely, a new platform and a new stapling device. Outcomes of robotic Roux-en-Y gastric bypass (rRYGB) and robotic sleeve gastrectomy (rSG) across this changing landscape have not been well studied, despite increasing popularity. The MBSAQIP database was analyzed over early (2015-2016) and late (2019-2020) time intervals. Patients who underwent rSG and rRYGB were identified, and the cohorts were matched for 26 preoperative characteristics using Propensity Score Matching Analysis. We then compared 30-day outcomes and bariatric-specific complications between the early and late time frames for rSG and rRYGB. 49,442 rSG were identified: 13,526 cases in the early time frame and 35,916 in the late time frame. The matched cohorts were 13,526 for the two groups. 30-day outcomes showed that in the late time frame, rSG was associated with lower rates of pulmonary complications (0.1% vs 0.3%, p < 0.001), readmissions (2.5% vs 3.6%, p < 0.001), interventions (0.6% vs 1.4%, p < 0.001), reoperations (0.7% vs 1.0%, p = 0.024), length of stay (1.36 ± 1.01days vs 1.76 ± 1.79days, p < 0.001), operative time (92.47 ± 41.70min vs102.76 ± 45.67min p < 0.001), staple line leaks (0.2% vs 0.4%, p = 0.001) and strictures (0.0% vs 0.2%, p < 0.001). Similarly, 21,933 rRYGB were found: 6,514 cases were identified in the early time frame and 15,419 in the late time frame. The matched cohorts were 6,513 for the two groups. 30-day outcomes revealed that the late time fame rRYGB was associated with lower rates of pulmonary complications (0.1% vs 0.3%, p = 0.012), readmissions (6.3% vs 7.2%, p = 0.050), interventions (2.0% vs 3.1%, p < 0.001), length of stay (1.69 ± 1.46days vs 2.13 ± 2.12days p < 0.001), postoperative bleeding (0.4% vs 0.7%, p = 0.001), stricture (0.4% vs 0.8%, p < 0.001) and anastomotic ulcer (0.2% vs 0.4%, p = 0.013). Compared to early robotic bariatric surgery outcomes, a significant reduction in pulmonary complications, readmissions, reoperations, interventions and length of stay were seen in 2019-20 after rSG and rRYGB. Potential contributing factors include increased surgical experience and advances in the robotic platform. A significant recent reduction in staple line leaks with faster operative times associated with rSG suggests that stapling technology has had a positive impact on patient outcomes.

Role of Brain Imaging in the Prediction of Intracerebral Hemorrhage Following Endovascular Therapy for Acute Stroke.

Currently most acute ischemic stroke patients presenting with a large vessel occlusion are treated with endovascular therapy (EVT), which results in high rates of successful recanalization. Despite this success, more than half of EVT-treated patients are significantly disabled 3 months later partly due to the occurrence of post-EVT intracerebral hemorrhage. Predicting post-EVT intracerebral hemorrhage is important for individualizing treatment strategies in clinical practice (eg, safe initiation of early antithrombotic therapies), as well as in selecting the optimal candidates for clinical trials that aim to reduce this deleterious outcome. Emerging data suggest that brain and vascular imaging biomarkers may be particularly relevant since they provide insights into the ongoing acute stroke pathophysiology. In this review/perspective, we summarize the accumulating literature on the role of cerebrovascular imaging biomarkers in predicting post-EVT-associated intracerebral hemorrhage. We focus on imaging acquired before EVT, during the EVT procedure, and in the early post-EVT time frames when new therapeutic therapies could be tested. Accounting for the complex pathophysiology of post-EVT-associated intracerebral hemorrhage, this review may provide some guidance for future prospective observational or therapeutic studies.

Study on the quasi-isentropic model for aluminized explosive driving the cylinder in the direction perpendicular to detonation wave propagation

A cylinder test was designed for the CL-20-based aluminized explosives to study the influence of aluminum (Al) powder properties on the explosives' metal driving performance in the direction perpendicular to detonation wave propagation. The research results showed that: in the direction perpendicular to detonation wave propagation, as the Al powder particle size became larger (in the range of 2–43 μm), the metal driving performance of the explosives grew stronger; the CL-20-based explosive containing 25% Al was much less capable of accelerating the metal than the formulation containing 15% Al. Considering the two-dimensional flow characteristics of the detonation products in the radial and axial directions as the aluminized explosive expands and drives the cylinder, a quasi-isentropic theoretical model for the aluminized explosive driving the cylinder was proposed. In the model, the calculation methods for the variations of the cylinder expansion velocity, Al reaction degree, and detonation product parameters with time, axial space, and radial space were developed. According to the experimental data of the cylinder test, the correctness of the proposed quasi-isentropic theoretical model was verified; the variation laws of the physical parameters, such as the pressure and temperature of the detonation products under different radial distributions in the cylinder with time and axial positions, were calculated. It was found that the pressure and temperature of the detonation products in the non-inner-wall place of the cylinder were significantly higher than those on the inner wall of the cylinder at the same axial position; the pressure and temperature of the detonation products on the inner wall decreased rapidly at the early timeframes; as the Al reaction proceeded, the pressure gradually turned to a constant value, and the temperature dropped slowly; for the CL-20-based explosives with 15% Al, the temperature of the detonation products in the non-inner-wall place rose slightly at first and then decreased slowly; for the formulation with 25% Al, the temperature of the detonation products in the non-inner-wall place kept rising at a small rate.

Relative Age Effect in Judo Competitions: Influence of Age, Weight Category, Sex, and Time Frames

This study was conducted to determine whether the relative age effect (RAE) is present in different age groups, weight categories, sexes, and across different time frames in international-level judo competition. A total of 9451 judo athletes competing at the Olympic Games and/or World Championships in the Cadet, Junior and/or Senior age groups between 1993 and 2020 were considered. Athletes' birthdate distributions were grouped in four quartiles (Q1: January-March; Q2: April-June; Q3: July-September; Q4: October-December) and compared to a day-corrected theoretical distribution using Chi-squared analysis. Poisson regression was also used to evaluate the ability to explain weekly birth count. RAE was more prevalent in males than females (p < .05), and for Cadets and Juniors compared to Seniors (p < .05). Heavyweight and middleweight categories presented RAEs in Senior and Junior males, while for females it was present in Cadet heavyweights (p < .05). RAE was more prevalent in recent years (2009-2021) for Senior male judo athletes (p < .05). Poisson analysis illustrated some nuanced information, including RAE detection during an earlier time frame, not readily apparent with the traditional analysis.

Commentary: Consensual ophthalmotonic reaction.

Intraocular pressure (IOP) change in the untreated fellow eye accompanied by a corresponding IOP reduction in the operated eye has been identified as the “consensual ophthalmotonic reaction” (COR), and the terminology was coined by Weekers in 1924.[1] This response was initially observed after contusion, ocular compression, tonography, and cauterization of the sclera.[2] In 1927, Wilmer published the first report on COR after a fistulating surgery in experimental animals.[3] After that, multiple studies have reported the possibility of IOP variation in the fellow eye following unilateral glaucoma surgery, including not only trabeculectomy, but glaucoma drainage device implantations, filtering canaloplasty, and microshunt implantations as well.[4] However, whether there is an IOP increase, decrease, or no change in the fellow eye after glaucoma surgery is still controversial. These contrasting results could be due to differences in the type of glaucoma, preoperative IOP, surgical technique, antimetabolite dosage and duration, time point of observation, and outflow facility of the untreated fellow eye. The postulated mechanisms behind COR include neuronal, hormonal, and cytokine regulation of aqueous flow dynamics.[5] Nevertheless, the exact mechanism is yet to be elucidated. A decrease in IOP in the fellow eye could be associated with improved patient compliance to the antiglaucoma therapy or the effect of systemic absorption of the medications. Also, it could result from a “regression to the mean” effect, as trabeculectomy is often planned when the IOP is high on the variation curve.[6] Regarding COR with topical medications, Newman et al.[7] observed that the IOP reduction in contralateral eyes was found to be associated with timolol only and not prostaglandins or carbonic anhydrase inhibitors. A similar decrease in IOP in the fellow eye has also been reported after laser trabeculoplasty, which might be due to the effects of the systemic release of humoral agents, such as matrix metalloproteinase, and improved medication compliance.[8] An increase in the fellow eye IOP following glaucoma surgery has been observed in the present study. We have also observed an IOP rise in a significant number of patients in the unoperated eye in the early postoperative period after unilateral trabeculectomy, though we do not have published data. Different theories have been postulated that may explain this finding. Weekers[1] explained the possible existence of COR in which activation of the nervous system increased the fellow eye aqueous production. Diestelhorst and Krieglstein[5] also postulated that unilateral filtration surgery triggers a central nervous system-mediated reflective increase in aqueous flow in the unoperated fellow eye to maintain physiological stability. In an animal experiment, a supraoptic controlling pathway has been suggested to lead to an IOP rise in response to water drinking after unilateral optic nerve sections.[9] A few studies described that underperfusion of the trabecular meshwork by aqueous humor in the operated eye and increased extracellular trabecular meshwork material deposition induces a reflex mechanism mediated by specialized cells in the scleral spur that can lead to decreased outflow in the fellow eye.[10] Another hypothesis was an increase in the prostaglandin level in response to the inflammation in the operated eye.[11] Other possible explanations include a postoperative presumed steroid response or withdrawal of antiglaucoma medications.[12] No studies have attributed the increase in IOP in the fellow eye to one factor. In the literature, post-surgical COR is found to occur at an earlier time frame than post-laser COR, which might suggest the role of mechanical triggers rather than chemical triggers in post-surgical COR. The predominance of one mechanism occurring due to a particular intervention may guide the IOP varia tion in the contralateral eye. Further prospective studies and a much more detailed macroscopic overview are needed to delineate the underlying mechanisms and the exact biological role of post-surgical COR. The take-home message is that the fellow eye needs to be carefully monitored after unilateral glaucoma surgery. The fellow eye may be the only eye with vision or the better eye of the two. Also, fellow eyes may be already glaucomatous, that failure to monitor and recognize IOP rise may delay appropriate management leading to glaucoma progression. It is recommended to inform the patient about the possibility of IOP variation in the other eye after glaucoma surgery and the need for multiple visits, especially in the early postoperative period. Another relevant message is that the fellow eyes should not be preferably used as a control in studies assessing the IOP outcomes of a particular treatment or intervention.

Abstract WP177: Effects Of The Oral Factor XIa Inhibitor Asundexian On Intracranial Bleeding Among Patients With Acute Non-Cardioembolic Ischemic Stroke: PACIFIC-Stroke Randomized Trial

Introduction: The phase 2 PACIFIC-Stroke trial of patients with acute non-cardioembolic ischemic stroke assessed asundexian, the oral small molecule Factor XIa inhibitor, versus placebo administered within 48h of ischemic stroke to prevent recurrent stroke. This trial uniquely included moderate and severe strokes, which were excluded from other early timeframe, secondary prevention trials of escalated antithrombotic therapy. The primary results suggest a reduction in recurrent ischemic stroke and TIA when added to antiplatelet therapy without an overall increase in intracranial hemorrhage (ICH)(in press at the Lancet ). In this post-hoc analysis, we will further characterize the observed ICH. Methods: PACIFIC-Stroke (NCT04304508) was an international, double-blind, placebo-controlled, phase 2 randomized trial enrolling 1808 participants and comparing three dosages (10mg, 20mg, or 50mg daily) of asundexian with placebo. Participants were randomized within 48h of the qualifying ischemic stroke, and all received background antiplatelet therapy chosen by the local investigator. Eligibility for Part A was limited to patients with NIHSS &lt;/=7 who did not receive thrombolysis or endovascular thrombectomy, and Part B allowed an NIHSS up to 15 and treatment with reperfusion therapy (if &gt;24 hours prior to randomization). Participants underwent MRIs within 72 hours of randomization and after 6 months. Results: In this presentation, we will further characterize the ICHs observed in the 1808 participants (1334 asundexian, 452 placebo) of the PACIFIC-Stroke trial. Further characterization will include timing, baseline stroke severity, post-thrombolysis/endovascular therapy status, asundexian dosing, and associated symptoms and radiological subtypes will be presented. Conclusions: Early anticoagulation of ischemic stroke patients with asundexian added to antiplatelet therapy was not associated with an increase in ICH compared to placebo, supporting the premise that inhibition of Factor XIa may prevent thrombosis without increasing bleeding. Further characterization of the observed ICHs associated with this novel drug compared to placebo will be presented.

Investigation of image-derived input functions for non-invasive quantification of myelin density using [11C]MeDAS PET

Multiple sclerosis (MS) is an inflammatory demyelinating disease. Current treatments are focussed on immune suppression to modulate pathogenic activity that causes myelin damage. New treatment strategies are needed to prevent demyelination and promote remyelination. Development of such myelin repair therapies require a sensitive and specific biomarker for efficacy evaluation. Recently, it has been shown that quantification of myelin density is possible using [11C]MeDAS PET. This method, however, requires arterial blood sampling to generate an arterial input function (AIF). As the invasive nature of arterial sampling will reduce clinical applicability, the purpose of this study was to assess whether an image-derived input function (IDIF) can be used as an alternative way to facilitate its routine clinical use.Six healthy controls and 11 MS patients underwent MRI and [11C]MeDAS PET with arterial blood sampling. The application of both population-based whole blood-to-plasma conversion and metabolite corrections were assessed for the AIF. Next, summed images of the early time frames (0–70 s) and the frame with the highest blood-brain contrast were used to generate IDIFs. IDIFs were created using either the hottest 2, 4, 6 or 12 voxels, or an isocontour of the hottest 10% voxels of the carotid artery. This was followed by blood-to-plasma conversion and metabolite correction of the IDIF.The application of a population-based metabolite correction of the AIF resulted in high correlations of tracer binding (Ki) within subjects, but variable bias across subjects. All IDIFs had a sharper and higher peak in the blood curves than the AIF, most likely due to dispersion during blood sampling. All IDIF methods resulted in similar high correlations within subjects (r = 0.95–0.98), but highly variable bias across subjects (mean slope=0.90–1.09).Therefore, both the use of population based blood-plasma and metabolite corrections and the generation of the image-derived whole-blood curve resulted in substantial bias in [11C]MeDAS PET quantification, due to high inter-subject variability. Consequently, when unbiased quantification of [11C]MeDAS PET data is required, individual AIF needs to be used.

Electroconductive scaffolds based on gelatin and PEDOT:PSS for cardiac regeneration

Electroconductive biomaterials have been emerged to support the recovery of the degenerated electrically conductive tissues, especially the cardiac ones after myocardial infarction. This work describes the development of electroconductive scaffolds for cardiac tissue regeneration by using a biocompatible and conductive polymer – i.e. poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) – combined with a biomimetic polymer network of gelatin. Our approach involves the use of dehydrothermal (DHT) treatment in vacuum conditions to fabricate suitably stable scaffolds without using any additional crosslinking agent. The resulting scaffolds mimic the Young modulus – an essential mechanical performance – of native cardiac tissue and are endowed with a well-interconnected porosity coupled with a good swelling ability and stability in physiological conditions. Additionally, the presence of PEDOT:PSS is able to enhance the electroconductivity of resulting materials. All the scaffolds are non-cytotoxic towards H9C2 cardiomyoblasts and the presence of PEDOT:PSS enhances cell adhesion – especially at early timeframes, an essential condition for a successful outcome after the implantation – proliferation, and spreading on scaffolds. Considering the permissive interaction of scaffolds with cardiomyoblasts, the present biomimetic and electroconductive scaffolds display potential applications as implantable biomaterials for regeneration of electroconductive tissues, especially cardiac tissue, and as a promising 3D tissue model for in vitro biomolecules screening.

Change across Time in L2 Intonation vs. Segments: A Longitudinal Study of the English of Ole Gunnar Solskjaer

Research on L1 to L2 transfer has mainly focused on segments, while less work has examined transfer in intonation patterns. Particularly, little research has investigated transfer patterns when the L1 has a lexical pitch contrast, such as tone or lexical pitch accent, and the L2 does not. The current investigation is a longitudinal study of the L2 English of an L1 Norwegian speaker, comparing two timeframes. One suprasegmental feature and one segmental feature are examined: rise–fall pitch accents and /z/, because Norwegian and English have different patterns for these features. The results showed that the speaker actually produced more pitch movements in the later timeframe, contrary to the hypothesis, and suggesting that he was hypercorrecting in the earlier timeframe. In the early timeframe, virtually no /z/ was produced with voicing, while in the later timeframe, about 50% of /z/ segments were voiced. This suggests that the speaker had created a new category for this sound over time. Implications for theories of L2 learning are discussed.

Surgery for Pituitary Tumor Apoplexy Is Associated with Rapid Headache and Cranial Nerve Improvement.

Pituitary tumor apoplexy (PTA) classically comprises sudden-onset headache, loss of vision, ophthalmoparesis, and decreased consciousness. It typically results from hemorrhage and/or infarction within a pituitary adenoma. Presentation is heterologous, and optimal management is debated. The time course of recovery of cranial nerve deficits (CNDs) and headaches is not well established. In this study, a retrospective series of consecutive patients with PTA managed at a single academic institution over a 22-year period is presented. Headaches at the time of surgery were more severe in the early and subacute surgical cohort and improved significantly within 72 h postoperatively (p < 0.01). At one year, 90% of CNDs affecting cranial nerves (CNs) 3, 4, and 6 had recovered, with no differences between early (<4 d), subacute (4–14 d), and delayed (>14 d) time-to-surgery cohorts. Remarkably, half recovered within three days. In total, 56% of CN2 deficits recovered, with the early surgery cohort including more severe deficits and recovering at a lower rate (p = 0.01). No correlation of time-to-surgery and rapidity of recovery of CNDs was observed (p = 0.65, 0.72). Surgery for PTA is associated with rapid recovery of CNDs in the early, subacute, and delayed time frames, and with rapid headache improvement in the early and subacute time frames in 50% or more of patients.

Recent Advances in the Development of Tetrazine Ligation Tools for Pretargeted Nuclear Imaging.

Tetrazine ligation has gained interest as a bio-orthogonal chemistry tool within the last decade. In nuclear medicine, tetrazine ligation is currently being explored for pretargeted approaches, which have the potential to revolutionize state-of-the-art theranostic strategies. Pretargeting has been shown to increase target-to-background ratios for radiopharmaceuticals based on nanomedicines, especially within early timeframes. This allows the use of radionuclides with short half-lives which are more suited for clinical applications. Pretargeting bears the potential to increase the therapeutic dose delivered to the target as well as reduce the respective dose to healthy tissue. Combined with the possibility to be applied for diagnostic imaging, pretargeting could be optimal for theranostic approaches. In this review, we highlight efforts that have been made to radiolabel tetrazines with an emphasis on imaging.

Atypical Lower Limb Mechanics During Weight Acceptance of Stair Descent at Different Time Frames After Anterior Cruciate Ligament Reconstruction

Background: An anterior cruciate ligament (ACL) rupture may result in poor sensorimotor knee control and, consequentially, adapted movement strategies to help maintain knee stability. Whether patients display atypical lower limb mechanics during weight acceptance of stair descent at different time frames after ACL reconstruction (ACLR) is unknown. Purpose: To compare the presence of atypical lower limb mechanics during the weight acceptance phase of stair descent among athletes at early, middle, and late time frames after unilateral ACLR. Study Design: Controlled laboratory study. Methods: A total of 49 athletes with ACLR were classified into 3 groups according to time after ACLR—early (<6 months; n = 17), middle (6-18 months; n = 16), and late (>18 months; n = 16)—and compared with asymptomatic athletes (control; n = 18). Sagittal plane hip, knee, and ankle angles; angular velocities; moments; and powers were compared between the ACLR groups’ injured and noninjured legs and the control group as well as between legs within groups using functional data analysis methods. Results: All 3 ACLR groups showed greater knee flexion angles and moments than the control group for injured and noninjured legs. For the other outcomes, the early group had, compared with the control group, less hip power absorption, more knee power absorption, lower ankle plantarflexion angle, lower ankle dorsiflexion moment, and less ankle power absorption for the injured leg and more knee power absorption and higher vertical ground reaction force for the noninjured leg. In addition, the late group showed differences from the control group for the injured leg revealing more knee power absorption and lower ankle plantarflexion angle. Only the early group took a longer time than the control group to complete weight acceptance and demonstrated asymmetry for multiple outcomes. Conclusion: Athletes with different time frames after ACLR revealed atypically large knee angles and moments during weight acceptance of stair descent for both the injured and the noninjured legs. These findings may express a chronically adapted strategy to increase knee control. In contrast, atypical hip and ankle mechanics seem restricted to an early time frame after ACLR. Clinical Relevance: Rehabilitation after ACLR should include early training in controlling weight acceptance. Including a control group is essential when evaluating movement patterns after ACLR because both legs may be affected.

Pupillary Light Reflex Metrics Differ in Adolescents with Acute Concussion VS. Persistent Post-Concussion Symptoms

Background: A potential objective measure that may assist in identifying vision disorders after concussion is the pupillary light reflex (PLR), which is under autonomic control and contributes to normal convergence and accommodative function which is altered after concussion. This study sought to compare pupillometry measures in adolescents with concussion initially presenting for care in the early acute time frame (≤ 2 weeks post-concussion) to those presenting in the later acute time frame (4 ± 1 weeks). Hypothesis: To determine whether PLR metrics are similar or different between athletes with concussion presenting earlier (≤ 2 weeks post-concussion) for care vs. those presenting later for care (4 ± 1 weeks). Methods: Athletes, ages 12-18 years, with a diagnosis of sport-related concussion (n = 110) were recruited. 89 concussed subjects had their PLR assessment performed at an early acute time point ≤ 2 weeks after concussion, while 21 concussed subjects had their first assessment at a later acute time point (4 week±1 week). Pupillary dynamics were measured in response to a brief, step-input, white light stimulus (154 ms duration; 180 micro watts power) via a Neuroptics PLR-3000 hand-held, infrared, automated, monocular pupillometer (Neuroptics, Irvine, CA). The means of the PLR metrics were compared between groups with one-way Student’s t test. Bonferroni correction was applied. Results: The baseline pupil diameter (mean ± SD) was significantly larger (p&lt;0.05) for the subjects seen later 4 ± 1 week (5.09 mm ± 0.63) as compared to the cohort of subjects who presented earlier within 2 weeks after injury (4.72 ± 0.79mm). Average constriction velocity ACV for the later-presenting cohort (3.35±0.45 mm/s) was significantly faster compared to the early-presenting cohort (3.04±0.59 mm/s). Similarly, maximum constriction velocity for the groups were significantly different (early 4.82±0.90 versus late 5.31±0.70 mm/s), even after Bonferroni correction (p&lt;0.05), with alpha of 0.025. All the other pupillometric parameters were not different from each other. Conclusion: When comparing adolescents with concussion presenting early in the acute phase ≤ 2 weeks after concussion to those presenting later in the acute timeframe to care 4±1 weeks, those presenting later demonstrate enhancement of certain PLR metrics, namely larger baseline pupil diameter and faster average constriction velocity (ACV) and maximum constriction velocity (MCV). Differences in these PLR metrics in those presenting later in the acute timeframe may represent findings in those who are more likely to have persisting post-concussion symptoms, potentially shedding light on pathophysiological underpinnings of lingering symptoms.