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Background Type 2 ketone-prone diabetes mellitus (T2KPDM) is thought to occur in men of African descent, with obesity who experienced prolonged hyperglycemia; the role of medication non-adherence as a contributing cause remains unstudied.Research design and methods This was a retrospective study of unique adults (>18 years) who sought emergency care one of four hospitals in the greater Detroit area. Patients were identified on the basis of a laboratory order for a ß-hydroxybutyrate concentration. Two research coordinators abstracted 119 data fields. Patients were divided into four phenotypes: (1) no prior DM, (2) type 2 DM without prior ketosis, (3) type 2 with prior ketosis and (4) type 1 DM. A ß-hydroxybutyrate >20 mg/dL defined diabetic ketoacidosis (DKA). A directed acyclic graph was constructed to diagram a causal pathway.Results Of 450 patients, 326 were non-type I and 37% of these had DKA. Concentrations of ß-hydroxybutyrate, glucose, bicarbonate were not different between non-type1 versus type 1 DM patients. Admission rates to the ICU and hospital lengths of stay were similar between the four phenotypes with DKA. We found no association with sex, race or body mass index. Unadjusted odds for DKA were significant for non-adherence (odds=1.74, 95% CI 1.08 to 2.21) arrival by Emergency Medical Services (odds=0.54, 95% CI 0.33 to 0.86) and private or Medicare insurance (odds=6.80, 95% CI 4.00 to 11.60). The median HbA1C was statistically higher in patients with DKA (median 11.3%) versus those without DKA (median 9.5%, Mann-Whitney U p

Abstract Background Lumbar degenerative spondylolisthesis (LDS), characterized as degeneration of the intervertebral disc and structural changes of the facet joints, is a condition with varying degrees of instability that may lead to pain, canal stenosis, and subsequent surgical intervention. However, the etiology of LDS remains inconclusive. Gut microbiome dysbiosis may stimulate systemic inflammation in various disorders. However, the role of such dysbiosis upon spine health remains under‐studied. The current study assessed the association of gut microbiome dysbiosis in symptomatic patients with or without LDS. Methods A cross‐sectional analysis within the framework of a prospective study was performed. DNA was extracted from fecal samples collected from adult symptomatic patients with (n = 21) and without LDS (n = 12). Alpha and beta diversity assessed differences in fecal microbial community between groups. Taxon‐by‐taxon analysis identified microbial features with differential relative abundance between groups. Subject demographics and imaging parameters were also assessed. Results There was no significant group differences in age, sex, race, body mass index, smoking/alcohol history, pain profiles, spinopelvic alignment, and Modic changes (p >0.05). LDS subjects had significantly higher disc degeneration severity (p = 0.018) and alpha diversity levels compared to non‐LDS subjects (p = 0.002–0.003). Significant differences in gut microbial community structure were observed between groups (p = 0.046). Subjects with LDS exhibited distinct differences at the phylum level, with a significantly higher Firmicutes to Bacteroidota ratio compared to non‐LDS (p = 0.003). Differential relative abundance analysis identified six taxa with significant differences between the two groups, with LDS demonstrating an increase in putative pro‐inflammatory bacteria (Dialister, CAG‐352) and a decrease in anti‐inflammatory bacteria (Slackia, Escherichia‐Shigella). Conclusion This study is the first to report a significant association of gut microbiome dysbiosis and LDS in symptomatic patients, noting pro‐inflammatory bacterial taxa. This work provides a foundation for future studies addressing the role of the gut microbiome in association with spine health and disease.

ABSTRACT Background and Aims Femoral artery access is widely used despite recent increase in radial access for percutaneous coronary interventions (PCI). Femoral artery closure devices are used to shorten vascular closure time and reduce bleeding. We sought to examine sex‐based outcomes of femoral artery vascular closure devices (VCD) in patients undergoing PCI. Methods We identified patients who had undergone PCI (n = 11,415) in the Indiana University Health Multicenter Cardiac Cath registry using femoral artery access. Clinical outcomes were compared between VCD and manual compression and analyzed according to sex. Patients with cardiogenic shock and left ventricular support devices were excluded. Results The use of any vascular closure device as compared to femoral artery manual compression was associated with a reduction in 72‐h bleeding events (adjusted odds ratio [OR]: 0.64; 95% confidence interval [CI]: 0.46–0.87). With manual compression, women had higher rates of 72‐h bleeding as compared to men (4.5% vs. 1.6%, p

Abstract Understanding the causes of mortality for a declining species is essential for developing effective conservation and management strategies, particularly when anthropogenic activities are the primary threat. Using a competing hazards framework allows for robust estimation of the cause‐specific variation in risk that may exist across multiple dimensions, such as time and individual. Here, we estimated cause‐specific rates of severe injury and mortality for North Atlantic right whales (Eubalaena glacialis), a critically endangered species that is currently in peril due to human‐caused interactions. We developed a multistate capture–recapture model that leveraged 30 years of intensive survey effort yielding sightings of individuals with injury assessments and necropsies of carcass recoveries. We examined variation in the hazard rates of severe injury and mortality due to entanglements in fishing gear and vessel strikes as explained by temporal patterns and the age and reproductive status of the individual. We found strong evidence for increased rates of severe entanglement injuries after 2013 and for females with calves, with consequently higher marginal mortality. The model results also suggested that despite vessel strikes causing a lower average rate of severe injuries, the higher mortality rate conditional on injury results in significant total mortality risk, particularly for females resting from a recent calving event. Large uncertainty in the estimation of carcass recovery rate for vessel strike deaths permeated into the apportionment of mortality causes. The increased rates of North Atlantic right whale mortality in the last decade, particularly for reproducing females, has been responsible for the severe decline in the species. By apportioning the human‐caused threats using a quantitative approach with estimation of relevant uncertainty, this work can guide development of conservation and management strategies to facilitate species recovery. Our approach is relevant to other monitored populations where cause‐specific injuries from multiple threats can be observed in live and dead individuals.

Background: Leg-length discrepancy (LLD) can lead to patient dissatisfaction and decreased function after total hip arthroplasty (THA). This study examines the impact of intraoperative fluoroscopy on the magnitude and incidence of LLD after THA. Methods: Patients undergoing primary THA were identified and stratified into cohorts based on one out of 4 surgical approaches and intraoperative fluoroscopy use. The most recent 100 patients matching each cohort were included. Preoperative and postoperative LLD was assessed radiographically via an interteardrop reference line to lesser trochanter measurement.Magnitude of LLD and the proportion of patients in each cohort with LLD >5 mm, >10 mm, and 15 mm were analyzed. Results: Four hundred patients were stratified into 4 equal cohorts. Overall, THA done with fluoroscopy yielded fewer leg length discrepancies than THA done without fluoroscopy. The anterior-based muscle sparing (ABMS) approach with fluoroscopy had significantly less postoperative LLD than the posterior approach without fluoroscopy (3.4 vs 5.1 mm, P < .01) and the ABMS approach in the lateral position without fluoroscopy (3.4 vs 4.8 mm, P = .03). For LLD >5 mm, the ABMS approach with fluoroscopy cohort had significantly fewer patients compared to the ABMS approach without fluoroscopy (23 vs 41, P < .01). For LLD >10 mm, the ABMS approach with fluoroscopy cohort had significantly fewer patients compared to the posterior approach without fluoroscopy (2 vs 15, P < .01). For LLD >15 mm, relative to the posterior approach without fluoroscopy, all other cohorts had significantly fewer outliers (P < .02). Conclusions: This study supplies evidence that use of intraoperative fluoroscopy is likely beneficial in reducing the magnitude of LLD following THA and reducing the incidence of outlier LLDs >5 mm, >10 mm, and

Background: The purpose of this study was to compare complication rates and clinical outcomes at 1 year or until death based on the surgical approach for total hip replacement in femoral neck fractures. Methods: This retrospective study was performed on 101 patients with displaced femoral neck fractures at our institution between 2005 and 2022. All surgeries were performed by fellowship-trained arthroplasty surgeons via either a posterior Kocher-Langenbeck approach, an abductor sparing anterolateral approach, or a direct anterior approach. Demographics were collected, as well as intraoperative characteristics, discharge information, and complications. Results: Thirty-seven patients underwent a direct anterior approach, 42 underwent an abductor sparing anterolateral approach, and 22 underwent a posterior approach, with no significant difference in demographics between the groups. Of patients, 43.3% were able to be discharged home, while 55.4% of patients went to subacute rehab or other nursing home facility. There was a 30.6% complication rate, a 7% reoperation rate, and a 0.9% dislocation rate. The posterior group was more likely to be discharged to rehab instead of home (82.0% compared to 48.6%, P = .0054) and had a significant increase in complication rate (P = .04). There was a 36.3% rate of transfusion in the posterior group compared to a 5.0% rate in the anterior group (P < .0001). Conclusions: Anterior-based total hip arthroplasty for femoral neck fractures in our series demonstrated a significantly lower rate of postoperative complications, a lower rate of transfusion, and a significantly higher rate of being discharged home. Level of Evidence: Level III.

BackgroundSocially isolated individuals tend to have less access to cognitively stimulating activities, which could adversely impact their cognitive health. The Internet-Based Conversational Engagement Clinical Trial (I-CONECT) intervention was designed to deliver online conversation sessions to socially isolated older old adults to prevent cognitive decline. The current study examined the intervention efficacy on participants’ weekly time spent out-of-home and their social interaction with family and friends.MethodsThe intervention group engaged in frequent conversations with trained interviewers via the Internet. Both intervention and control group participants received 10-min weekly phone check-in calls over 48 weeks, during which they were asked to self-report their time (in hours) spent out of home and whether they had contacted family or friends during this week (yes/no). Linear mixed-effect models for repeated measures were run for time spent out-of-home, and mixed-effect models with a logistic link for contact with family and friends. The intervention effect was modeled by including an interaction term of time (measured in weeks) and group assignments (intervention vs. control). We ran subgroup analyses for participants with normal cognition (NC) and mild cognitive impairment (MCI). All models controlled for age, sex, race, education, and the historical event of COVID-19.Results5,495 weekly records were included in the analysis. The main effect of time was statistically significant (p

IntroductionMeningiomas are the most common primary central nervous system (CNS) tumor in adults, comprising one-third of all primary adult CNS tumors. Although several recent publications have identified molecular alterations in meningioma including characteristic mutations, copy number alterations, and gene expression signatures, our understanding of the drivers of meningioma recurrence is limited.ObjectiveTo identify gene expression signatures of 1p-22q-NF2- meningioma recurrence, with concurrent biallelic inactivation of NF2 and loss of chr1p that are heterogenous but enriched for recurrent meningiomas.MethodsTranscriptomic alterations present in recurrent versus primary 1p-22q-NF2- meningiomas were identified using RNA sequencing (RNA-seq) data in a clinically annotated cohort.ResultsRecurrent 1p-22q-NF2- meningiomas were enriched for a newly identified GSTM1 null genotype compared to primary meningiomas that showed variable GSTM1 expression and independent external validation was performed.ConclusionsThe GSTM1 null genotype is a novel biomarker of 1p-22q-NF2- meningioma recurrence that resolves heterogeneity in existing meningioma subtypes and may be used to guide future clinical management decisions on extent of treatment to improve patient outcomes.

ABSTRACTEmerging evidence indicates that antibiotic-induced dysbiosis can play an etiological role in the pathogenesis of neuropsychiatric disorders. However, most of this evidence comes from rodent models. The objective of this study was to evaluate if antibiotic-induced gut dysbiosis can elicit changes in gut metabolites and behavior indicative of gut-brain axis disruption in common marmosets (Callithrix jacchus) – a nonhuman primate model often used to study sociability and stress. We were able to successfully induce dysbiosis in marmosets using a custom antibiotic cocktail (vancomycin, enrofloxacin and neomycin) administered orally for 28 days. This gut dysbiosis altered gut metabolite profiles, behavior, and stress reactivity. Increase in gut Fusobacterium spp. post-antibiotic administration was a novel dysbiotic response and has not been observed in any rodent or human studies to date. There were significant changes in concentrations of several gut metabolites which are either neurotransmitters (e.g., GABA and serotonin) or have been found to be moderators of gut-brain axis communication in rodent models (e.g., short-chain fatty acids and bile acids). There was an increase in affiliative behavior and sociability in antibiotic-administered marmosets, which might be a coping mechanism in response to gut dysbiosis-induced stress. Increase in urinary cortisol levels after multiple stressors provides more definitive proof that this model of dysbiosis may cause disrupted communication between gut and brain in common marmosets. This study is a first attempt to establish common marmosets as a novel model to study the impact of severe gut dysbiosis on gut-brain axis cross-talk and behavior.

Background Orthokeratinized odontogenic cyst (OOC) is a rare developmental odontogenic cyst that is clinically and histomorphologically different than odontogenic keratocyst (OKC).Case Description OOC is a distinct entity from OKC with a unique biological behavior, pathogenesis, and prognosis. The distinction between these entities is paramount because unlike OKCs, OOCs rarely recur after simple enucleation and are not associated with nevoid basal cell carcinoma syndrome. We present a case of an 8-year-old male with an OOC of the right posterior mandible along with a differential diagnosis and discussion of OOCs and its common mimics.

Per- and polyfluoroalkyl substances (PFASs) are a large class of compounds used in a variety of processes and consumer products. Their unique chemical properties make them ubiquitous and persistent environmental contaminants while also making them economically viable and socially convenient. To date, several reviews have been published to synthesize information regarding the immunotoxic effects of PFASs on the adaptive immune system. However, these reviews often do not include data on the impact of these compounds on innate immunity. Here, current literature is reviewed to identify and incorporate data regarding the effects of PFASs on innate immunity in humans, experimental models, and wildlife. Known mechanisms by which PFASs modulate innate immune function are also reviewed, including disruption of cell signaling, metabolism, and tissue-level effects. For PFASs where innate immune data are available, results are equivocal, raising additional questions about common mechanisms or pathways of toxicity, but highlighting that the innate immune system within several species can be perturbed by exposure to PFASs. Recommendations are provided for future research to inform hazard identification, risk assessment, and risk management practices for PFASs to protect the immune systems of exposed organisms as well as environmental health.

Most of the genome is transcribed into RNA but only 2% of the sequence codes for proteins. Non-coding RNA transcripts include a very large number of long noncoding RNAs (lncRNAs). A growing number of identified lncRNAs operate in cellular stress responses, for example in response to hypoxia, genotoxic stress, and oxidative stress. Additionally, lncRNA plays important roles in epigenetic mechanisms operating at chromatin and in maintaining chromatin architecture. Here, we address three lncRNA topics that have had significant recent advances. The first is an emerging role for many lncRNAs in cellular stress responses. The second is the development of high throughput screening assays to develop causal relationships between lncRNAs across the genome with cellular functions. Finally, we turn to recent advances in understanding the role of lncRNAs in regulating chromatin architecture and epigenetics, advances that build on some of the earliest work linking RNA to chromatin architecture.

The area burned by wildfires in Canada in 2023 is unprecedented in historical records. To help ensure the safety of communities and support the mobilization of firefighting resources, rapid detection of areas affected by wildfires is required. Satellite data are ideally suited to provide near real-time wildfire information over large areas. At the same time, clouds, smoke, and haze can obscure the collection of observations from sensors typically used for mapping purposes. Established methods using coarse spatial resolution satellites (e.g., MODIS, VIIRS) rely upon the combination of daily revisit to enable the rapid and reliable detection of large active fires, in full or in part, and the application of modeling (including spatial buffering) to infer additional, yet still obscured, areas. While timely, these initial maps of wildfire-impacted areas do not capture small fires (those smaller than 200 ha) and, importantly, are not intended to differentiate unburned areas within fire perimeters. To address these limitations, we used data from Sentinel-2A and -2B, and Landsat-8 and -9, which form a virtual constellation of four satellites to revisit and map burned area in Canada's forested ecosystems for the 2023 fire season. Availing upon the high temporal data density and using the Tracking Intra- and Inter-year Change algorithm (TIIC), an aggregate seasonal mapping of wildfires resulted in a total area affected by wildfires in 2023 of 12.74 Mha. Within this total area, 9.51 Mha of treed land cover was impacted. Shrubs and wetlands comprised most of the remaining non-treed area that was burned. Using a 2022 map of aboveground treed biomass (AGB), approximately 0.649 Pg of AGB was impacted by 2023 wildfires, representing an 11-fold increase in AGB impacts relative to a long-term annual average of treed AGB loss. Differences between the estimate of total burned area reported herein and the total burned area indicated by the Natural Resources Canada (NRCan) Fire M3 hotspot fire perimeters (18.64 Mha) were analyzed. Overall, estimates of burned area differed by 5.9 Mha, including over 1.13 Mha of water identified as burned within the NRCan perimeters. Differences in land cover and AGB impacts between the two products were also investigated and quantified. TIIC enables the near-continuous capture of areas impacted by fire through the fire season, allowing for within-year refinement of total burned area, rapid interrogation of land cover types impacted, and estimation of associated biomass consequences.

Arrhythmogenic cardiomyopathy is a severe genetic heart muscle disease characterized by fibro-fatty replacement of the myocardium. Pathogenic variants causal for this disease are mainly located in desmosomal genes, including desmoplakin (DSP). Renal epithelial cells were isolated from a patient carrying the heterozygous c.817C>T (p.Q273*, nonsense) pathogenic variant in DSP, and subsequently reprogrammed using the Cytotune®-iPS 2.0 Sendai Reprogramming Kit. An isogenic control line was generated using CRISPR/Cas9 genome editing. The resulting induced pluripotent stem cell lines were characterized and displayed the required traits for in vitro disease modeling.

Background: The purpose of this study is to compare 30-day perioperative outcomes following treatment of intertrochanteric (IT) fractures with intramedullary nail (IMN), total hip arthroplasty (THA), or hemiarthroplasty (HA). Methods: Using the National Surgical Quality Improvement Program database, we conducted a retrospective cohort study of patients who had sustained an IT fracture treated with primary IMN, THA, or HA between 2017 and 2020. International Classification of Diseases, 10th Revision codes S72.141-S72.146, subtypes A through C, were used to identify eligible patients and were cross-referenced to primary Current Procedural Terminology codes, used to identify the following procedure types: 27245: IMN; 27130: THA; and 27236: HA. Revision cases and patients who underwent arthroplasty for osteoarthritis were excluded. Outcomes of interest included reoperation, readmission, operative time, length of stay, and major and minor complications. Multivariate regression was used to evaluate differences in postoperative outcomes between groups. Results: There were 29,809 IT fractures treated with IMN (94.6%), 1493 treated with HA (4.7%), and 217 treated with THA (0.70%). There was a statistically significant increase in 30-day reoperation rates (adjusted odds ratio [aOR] = 1.99 [95% confidence interval = 1.51, 2.63], P < .001) when combining all arthroplasty patients compared to IMN. There was no statistically significant difference in the overall complication rate between IMN (13.58%) and HA (14.60%, aOR = 1.09, P = .315) or THA (11.98%, aOR = 1.00, P = .998). When compared to IMN (0.12%), there was a statistically significantly decreased need for transfusion in the HA group (aOR = 0.71 [95% confidence interval = 0.61, 0.80], P < .001). Conclusions: Primary HA is associated with an increased 30-day reoperation rate and decreased need for blood transfusion, but there were no other significant differences in postoperative morbidity identified among IMN, THA, and HA in the treatment of IT fractures. Given the challenges and inferior outcomes associated with conversion arthroplasty, the lack of significant difference in morbidity between the 3 groups suggests that primary arthroplasty may be a safe and viable treatment option in selected patients with IT fractures. Comparative studies with longer clinical follow-up will be necessary to establish the appropriate indications and further evaluate the clinical outcomes of primary arthroplasty in the treatment of IT fractures.

Abstract. Introduction:. Chronic overlapping pain conditions (COPCs), such as chronic low back pain (cLBP) and fibromyalgia, frequently cooccur and incur substantial healthcare costs. However, to date, much focus has been placed on individual anatomically based chronic pain conditions, whereas little is known about the mechanisms underlying progression to multiple (more than 1) COPCs. This study aims to address the gap by investigating the role of common and modifiable risk factors, specifically sleep and circadian rhythm disturbances, in the development of multiple COPCs. Methods:. The study will enroll 300 participants with cLBP, including 200 with cLBP only and 100 with cLBP plus other COPCs (ie, fibromyalgia, temporomandibular disorders, irritable bowel syndrome, and chronic headaches) and follow them up for 12 months. Sleep and circadian rhythms will be assessed using wireless sleep electroencephalography, 24-hour evaluation of the rhythm of urinary 6-sulfatoxymelatonin, actigraphy, and sleep diaries. Pain amplification using quantitative sensory testing, psychological distress using validated self-report measures, and the number of pain sites using a pain body map will also be assessed. Perspectives:. This research aims to (1) comprehensively characterize sleep/circadian disturbances in individuals with single and multiple COPCs using multimodal in-home assessments; (2) examine the associations between sleep/circadian disturbances, changes in pain amplification, and psychological distress; and (3) investigate the relationship among these factors and the progression in the number of pain sites, a proxy for multiple COPCs. The findings will provide insights into the mechanisms leading to multiple COPCs, potentially informing treatment and prevention strategies for these complex conditions.

Objective: Pharmacologic or genetic manipulation of O-GlcNAcylation, an intracellular, single sugar post-translational modification, are difficult to interpret due to the pleotropic nature of O-GlcNAc and the vast signaling pathways it regulates. Method: To address the pleotropic nature of O-GlcNAc, we employed either OGT (O-GlcNAc transferase), OGA (O-GlcNAcase) liver knockouts, or pharmacological inhibition of OGA coupled with multi-Omics analysis and bioinformatics. Results: We identified numerous genes, proteins, phospho-proteins, or metabolites that were either inversely or equivalently changed between conditions. Moreover, we identified pathways in OGT knockout samples associated with increased aneuploidy. To test and validate these pathways, we induced liver growth in OGT knockouts by partial hepatectomy. OGT knockout livers showed a robust aneuploidy phenotype with disruptions in mitosis, nutrient sensing, protein metabolism/amino acid metabolism, stress response, and HIPPO signaling demonstrating how OGT is essential in controlling aneuploidy pathways. Conclusion: These data show how a multi-Omics platform can disentangle the pleotropic nature of O-GlcNAc to discern how OGT fine-tunes multiple cellular pathways involved in aneuploidy.

Abstract Habitat‐based approaches to animal conservation are bolstered by an understanding of resource selection, that is, use of resources (i.e., habitat features) relative to their availability in the environment. Quantifying resource selection is especially valuable when data characterizing animal space use are limited, as is often the case with mobile and/or cryptic species. Documenting associations with habitat features can better inform management in space in time, while also revealing key insight into movement ecology and behavior. Here, we evaluate resource selection by a megaomnivore whose highly mobile nature within marine habitats has resulted in an incomplete understanding of drivers of space use. We used satellite telemetry to track 29 green turtles (Chelonia mydas) from an eastern Pacific foraging aggregation in San Diego Bay, California, USA during 2013–2023. Tracking produced 5023 Fastloc‐GPS points which we used to model selection for local environmental resources relative to their availability. We employed logistic models to evaluate associations with seagrass, bathymetry, and water temperatures, implementing a framework that additionally allowed us to explore the roles of season, diel period, and turtle body size. Our methods demonstrate an approach for down‐weighting observations according to assumed telemetry error and autocorrelation. Results from fine‐scale resource selection models provide evidence that green turtles in San Diego Bay select for eelgrass meadows (Zostera marina), particularly during the warmest months of the year, but the strength of this selection changes from day to night. We additionally found day–night shifts in depth and temperature selection that changed with turtle body size and season. We discuss these findings in the context of diel patterns in resting and foraging behavior in addition to seasonal changes in thermally sensitive metabolic rates. Our study documents resource associations and provides quantitative information for the management of sea turtle foraging populations and their habitats. We offer key insight into habitat use by green turtles in the eastern Pacific at a pivotal time when multiple indicators point to population growth and expansion within the region.

This viewpoint reviews the empirical evidence regarding the association between social media use and well-being, including life satisfaction and affective well-being, and the association between social media use and ill-being, including loneliness, anxiety, and depressive symptomology. To frame this discussion, this viewpoint will present 10 widely believed myths about social media, each drawn from popular discourse on the topic. In rebuttal, this viewpoint will offer a warranted claim supported by the research. The goal is to bring popular beliefs into dialogue with state-of-the-art quantitative social scientific evidence. It is the intention of this viewpoint to provide a more accurate and nuanced claim to challenge each myth. This viewpoint will bring attention to the importance of using rigorous scientific evidence to inform public debates about social media use and well-being, especially among adolescents and young adults.

As part of U.S. national efforts to combat the detrimental effect of global climate change, the National Institute of Standards and Technology (NIST) was recently tasked to support efforts in direct air capture (DAC) of carbon dioxide research and deployment. In order to develop test procedures, materials, and documentary standards, key characterization methods relevant to DAC materials have been investigated and used to identify desirable properties for a potential Standard Reference Material (SRM). Select amine-supported materials that previously showed potential for DAC applications have been characterized using commonly available laboratory methods. Further insights into the adsorption characteristics have been gained from developing and applying more specialized characterization tools ideal for probing low concentrations of carbon dioxide. A broad suite of capabilities that examine relevant properties under appropriate conditions gives the most profound insights into a material’s specific performance. We advocate for even more specialized capabilities to be developed and standardized to quantitatively monitor the interactions of CO2 with molecular species in complex and often disordered systems to advance DAC and support carbon dioxide reduction (CDR) in general.

Abstract Earth's forests are continually monitored by both the satellite record and the lived experiences of nearly 2 billion forest‐proximate peoples. Generally, the satellite record summarizes production estimates, such as percent tree cover, at regular, relatively coarse scales. Conversely, local perceptions tend to capture changes at irregular and very fine scales. While the utility of both of these sources of information has been widely demonstrated in isolation, little work has explored in what contexts they are expected to correlate or deviate, or how they might be quantitatively integrated. Here, we collect gridded information on community perceived and remotely sensed mangrove cover change across 719 0.5‐km grids in Pemba Island, Tanzania. We reveal variation in the association between these two data sources across different wards (shehia) and explore the reasons for this variation using interviews and direct observation. We find that shehia with the greatest alignment between perceived and remotely sensed mangrove change tended to have little planting or natural regeneration of mangrove propagules and large areas of complete cover loss. Alternatively, in shehia with the lowest alignment, we find high levels of natural and/or human‐assisted mangrove recolonization and selective harvesting of individual trees and branches. These findings indicate that the alignment between local knowledge and satellite observations of mangrove cover change systematically increases with the scale of change in this system. Finally, we demonstrate a practical workflow for quantitatively leveraging these misalignments by optimizing across both data sources to identify restoration priority areas.

Abstract Background Organisms frequently experience environmental stresses that occur in predictable patterns and combinations. For wild Saccharomyces cerevisiae yeast growing in natural environments, cells may experience high osmotic stress when they first enter broken fruit, followed by high ethanol levels during fermentation, and then finally high levels of oxidative stress resulting from respiration of ethanol. Yeast have adapted to these patterns by evolving sophisticated “cross protection” mechanisms, where mild ‘primary’ doses of one stress can enhance tolerance to severe doses of a different ‘secondary’ stress. For example, in many yeast strains, mild osmotic or mild ethanol stresses cross protect against severe oxidative stress, which likely reflects an anticipatory response important for high fitness in nature. Results During the course of genetic mapping studies aimed at understanding the mechanisms underlying natural variation in ethanol-induced cross protection against H2O2, we found that a key H2O2 scavenging enzyme, cytosolic catalase T (Ctt1p), was absolutely essential for cross protection in a wild oak strain. This suggested the absence of other compensatory mechanisms for acquiring H2O2 resistance in that strain background under those conditions. In this study, we found surprising heterogeneity across diverse yeast strains in whether CTT1 function was fully necessary for acquired H2O2 resistance. Some strains exhibited partial dispensability of CTT1 when ethanol and/or salt were used as mild stressors, suggesting that compensatory peroxidases may play a role in acquired stress resistance in certain genetic backgrounds. We leveraged global transcriptional responses to ethanol and salt stresses in strains with different levels of CTT1 dispensability, allowing us to identify possible regulators of these alternative peroxidases and acquired stress resistance in general. Conclusions Ultimately, this study highlights how superficially similar traits can have different underlying molecular foundations and provides a framework for understanding the diversity and regulation of stress defense mechanisms.

Abstract Deletion of the maternal UBE3A allele causes Angelman syndrome (AS); because paternal UBE3A is epigenetically silenced by a long non-coding antisense (UBE3A-ATS) in neurons, this nearly eliminates UBE3A protein in the brain. Reactivating paternal UBE3A holds promise for treating AS. We previously showed topoisomerase inhibitors can reactivate paternal UBE3A, but their therapeutic challenges prompted our search for small molecule unsilencers with a different mechanism of action. Here, we found that (S)-PHA533533 acts through a novel mechanism to significantly increase paternal Ube3a mRNA and UBE3A protein levels while downregulating Ube3a-ATS in primary neurons derived from AS model mice. Furthermore, peripheral delivery of (S)-PHA533533 in AS model mice induces widespread neuronal UBE3A expression. Finally, we show that (S)-PHA533533 unsilences paternal UBE3A in AS patient-derived neurons, highlighting its translational potential. Our findings provide a lead for developing a small molecule treatment for AS that could be safe, non-invasively delivered, and capable of brain-wide unsilencing of paternal UBE3A.

Abstract Background Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after TNT may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes. Methods In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N +) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N + vs N0) and distance from anal verge (0–4; 4–8; 8–12 cm). Patients will be randomized to receive neoadjuvant long-course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3–4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8–12 (± 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 312 evaluable patients (156 per arm) will provide statistical power of 90.5% to detect a 17% increase in cCR rate, at a one-sided alpha = 0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse event rates. Biospecimens including archival tumor tissue, plasma and buffy coat, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and had accrued 330 patients as of May 2024. Study support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Discussion Building on data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed The Janus Rectal Cancer Trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer. Trial registration Clinicaltrials.gov ID: NCT05610163; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG).

Background: Superficial fungal foot infection is an infectious disease caused by dermatophyte, Candida spp., and mold. Risk factors are thought due to poor personal hygiene, frequent used of closed shoes, and high physical activity. Purpose: Investigate the profile and the risk factors of superficial fungal foot infections in military students. Methods: This is a cross-sectional study. Inclusion criteria for this study were navy military students with lesions on their feet. Result: This study involved 194 students as the populations with 97 students as the sample of the study. The average age were 17-25 years old, and male students being the major. Erythema and scale were found in the plantar and interdigital pedis. Students with good personal hygiene were 81 students among 97 students (83,5%). Wearing closed shoes for > 8 hours were found in 72 students among 97 students (74.2%). Most of the students exhibit a high physical activity with an average score of 26,880 MET minutes/week. Positive KOH 20% and cultures were found in 30 students (30.9%). Negative KOH 20% and positive culture were found in 27 students (27.8%). Positive KOH 20% and negative cultures were found in 9 students (9.3%). Negative KOH 20% and negative fungal culture results were found in 31 students (31,9%). Mold was the predominant fungal type. Conclusion: The students had good personal hygiene. The average wears closed shoes for >8 hours. Mold was the predominant fungal type in this study.

Abstract Introduction Following NOVA (part 1) and the approval of the subcutaneous (SC) route of administration of natalizumab by the European Medicines Agency, an extension phase of the NOVA phase IIIb study (part 2) was initiated to collect patient preference data for SC versus intravenous (IV) dosing in patients receiving every-6-week (Q6W) dosing of natalizumab. This study was performed to evaluate patient preference for SC versus IV natalizumab administration and explore the efficacy, safety, and pharmacology characteristics of both routes of administration. Methods In part 2, participants received natalizumab (Tysabri®) 300 mg via IV infusion Q6W for 36 weeks and then were randomized to 48 weeks of crossover treatment (24 weeks SC Q6W and 24 weeks IV Q6W, or vice versa). The primary endpoint was the proportion of participants who indicated a preference for natalizumab SC administration on the Patient Preference Questionnaire. Results A total of 153 participants were randomized in NOVA part 2. Of 123 with patient preference data, 108 (87.8%) preferred the SC route of administration for natalizumab over the IV route; 102 (82.9%) specified “requires less time in the clinic” as the reason for the SC preference. Conclusion In NOVA (part 2), most participants on Q6W dosing of natalizumab preferred SC administration versus IV administration. ClinicalTrials.gov NCT03689972. Infographic

Objective: The study objective was to determine if intraoperative peritoneal catheter placement is associated with improved outcomes in neonates undergoing high-risk cardiac surgery with cardiopulmonary bypass. Methods: This propensity score–matched retrospective study used data from 22 academic pediatric cardiac intensive care units. Consecutive neonates undergoing Society of Thoracic Surgeons–European Association for Cardio-Thoracic Surgery category 3 to 5 cardiac surgery with cardiopulmonary bypass at centers participating in the NEonatal and Pediatric Heart Renal Outcomes Network collaborative were studied to determine the association of the use of an intraoperative placed peritoneal catheter for dialysis or passive drainage with clinical outcomes, including the duration of mechanical ventilation. Results: Among 1490 eligible neonates in the NEonatal and Pediatric Heart Renal Outcomes Network dataset, a propensity-matched analysis was used to compare 395 patients with peritoneal catheter placement with 628 patients without peritoneal catheter placement. Time to extubation and most clinical outcomes were similar. Postoperative length of stay was 5 days longer in the peritoneal catheter placement cohort (17 vs 22 days, P = .001). There was a 50% higher incidence of moderate to severe acute kidney injury in the no-peritoneal catheter cohort (12% vs 18%, P = .02). Subgroup analyses between specific treatments and in highest risk patients yielded similar associations. Conclusions: This study does not demonstrate improved outcomes among neonates with placement of a peritoneal catheter during cardiac surgery. Outcomes were similar apart from longer hospital stay in the peritoneal catheter cohort. The no-peritoneal catheter cohort had a 50% higher incidence of moderate to severe acute kidney injury (12% vs 18%). This analysis does not support indiscriminate peritoneal catheter use, although it may support the utility for postoperative fluid removal among neonates at risk for acute kidney injury. A multicenter controlled trial may better elucidate peritoneal catheter effects.

Abstract The mechanism by which subarachnoid hemorrhage (SAH) leads to chronic neurologic deficits is unclear. One possibility is that blood activates microglia to drive inflammation that leads to synaptic loss and impaired brain function. Using the endovascular perforation model of SAH in rats, we investigated short-term effects on microglia together with long-term effects on EEG and neurologic function for up to 3 months. Within the first week, microglia were increased both at the site of injury and diffusely across the cortex (2.5-fold increase in SAH compared to controls, p = 0.012). Concomitantly, EEGs from SAH animals showed focal increases in slow wave activity and diffuse reduction in fast activity. When expressed as a fast-slow spectral ratio, there were significant interactions between group and time (p

Abstract Mutations in the FOXF1 gene, a key transcriptional regulator of pulmonary vascular development, cause Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins, a lethal lung disease affecting newborns and infants. Identification of new FOXF1 upstream regulatory elements is critical to explain why frequent non-coding FOXF1 deletions are linked to the disease. Herein, we use multiome single-nuclei RNA and ATAC sequencing of mouse and human patient lungs to identify four conserved endothelial and mesenchymal FOXF1 enhancers. We demonstrate that endothelial FOXF1 enhancers are autoactivated, whereas mesenchymal FOXF1 enhancers are regulated by EBF1 and GLI1. The cell-specificity of FOXF1 enhancers is validated by disrupting these enhancers in mouse embryonic stem cells using CRISPR/Cpf1 genome editing followed by lineage-tracing of mutant embryonic stem cells in mouse embryos using blastocyst complementation. This study resolves an important clinical question why frequent non-coding FOXF1 deletions that interfere with endothelial and mesenchymal enhancers can lead to the disease.

The ecology of macrofauna on the sandy bottom of oceanic islands in the tropics has rarely been studied. The present study was conducted at Isla del Coco, Costa Rica, a tropical oceanic island, to determine how the soft-bottom macrofauna assemblages vary along different levels of ocean exposure and their associated environmental conditions. The macrofauna was collected from five grabs at each of the 27 stations (between 3 and 75 m deep) in April 2010. The broad-scale pattern consists of a gradual increase in the complexity of assemblages (taxonomical or feeding guilds in the sediment) from the inner part to the outside of the bays. The leading determinant of this pattern was the interplay between ocean exposure and sediment variation with depth that produces habitat heterogeneity. The main taxa responsible for differences between ocean exposure zones were the polychaetes Westheidesyllis heterocirrata and Magelona californica, the filter-feeding bivalve Gouldia californica, and the predatory isopod Eurydice caudata. Coarse bottoms had more mobile predators and suspension feeders, whereas passive suspension feeders or subsurface deposit feeders dominated fine sands. The deeper stations were dominated by organisms feeding actively on particles from the water or on the sediment surface. Moreover, more feeding guilds were found in deeper waters. Additionally, at the small-scale view (grabs within each station), macrofauna composition evidences a mosaic pattern, mainly at the inner and middle of the bays, caused by biological or environmental disturbances.

Abstract Background Autism spectrum disorder (ASD) is currently diagnosed in approximately 1 in 44 children in the United States, based on a wide array of symptoms, including sensory dysfunction and abnormal language development. Boys are diagnosed ~ 3.8 times more frequently than girls. Auditory temporal processing is crucial for speech recognition and language development. Abnormal development of temporal processing may account for ASD language impairments. Sex differences in the development of temporal processing may underlie the differences in language outcomes in male and female children with ASD. To understand mechanisms of potential sex differences in temporal processing requires a preclinical model. However, there are no studies that have addressed sex differences in temporal processing across development in any animal model of ASD. Methods To fill this major gap, we compared the development of auditory temporal processing in male and female wildtype (WT) and Fmr1 knock-out (KO) mice, a model of Fragile X Syndrome (FXS), a leading genetic cause of ASD-associated behaviors. Using epidural screw electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at young (postnatal (p)21 and p30) and adult (p60) ages from both auditory and frontal cortices of awake, freely moving mice. Results The results show that ERP amplitudes were enhanced in both sexes of Fmr1 KO mice across development compared to WT counterparts, with greater enhancement in adult female than adult male KO mice. Gap-ASSR deficits were seen in the frontal, but not auditory, cortex in early development (p21) in female KO mice. Unlike male KO mice, female KO mice show WT-like temporal processing at p30. There were no temporal processing deficits in the adult mice of both sexes. Conclusions These results show a sex difference in the developmental trajectories of temporal processing and hypersensitive responses in Fmr1 KO mice. Male KO mice show slower maturation of temporal processing than females. Female KO mice show stronger hypersensitive responses than males later in development. The differences in maturation rates of temporal processing and hypersensitive responses during various critical periods of development may lead to sex differences in language function, arousal and anxiety in FXS.

Abstract Background In 2021 and 2023, the World Health Organization approved RTS,S/AS01 and R21/Matrix M malaria vaccines, respectively, for routine immunization of children in African countries with moderate to high transmission. These vaccines are made of Plasmodium falciparum circumsporozoite protein (PfCSP), but polymorphisms in the gene raise concerns regarding strain-specific responses and the long-term efficacy of these vaccines. This study assessed the Pfcsp genetic diversity, population structure and signatures of selection among parasites from areas of different malaria transmission intensities in Mainland Tanzania, to generate baseline data before the introduction of the malaria vaccines in the country. Methods The analysis involved 589 whole genome sequences generated by and as part of the MalariaGEN Community Project. The samples were collected between 2013 and January 2015 from five regions of Mainland Tanzania: Morogoro and Tanga (Muheza) (moderate transmission areas), and Kagera (Muleba), Lindi (Nachingwea), and Kigoma (Ujiji) (high transmission areas). Wright’s inbreeding coefficient (Fws), Wright’s fixation index (FST), principal component analysis, nucleotide diversity, and Tajima’s D were used to assess within-host parasite diversity, population structure and natural selection. Results Based on Fws (

Abstract Background Emerging artemisinin partial resistance and diagnostic resistance are a threat to malaria control in Africa. Plasmodium falciparum kelch13 (k13) propeller-domain mutations that confer artemisinin partial resistance have emerged in Africa. k13-561H was initially described at a frequency of 7.4% from Masaka in 2014–2015, but not present in nearby Rukara. By 2018, 19.6% of isolates in Masaka and 22% of isolates in Rukara contained the mutation. Longitudinal monitoring is essential to inform control efforts. In Rukara, an assessment was conducted to evaluate recent k13-561H prevalence changes, as well as other key mutations. Prevalence of hrp2/3 deletions was also assessed. Methods Samples collected in Rukara in 2021 were genotyped for key artemisinin and partner drug resistance mutations using molecular inversion probe assays and for hrp2/3 deletions using qPCR. Results Clinically validated k13 artemisinin partial resistance mutations continue to increase in prevalence with the overall level of mutant infections reaching 32% in Rwanda. The increase appears to be due to the rapid emergence of k13-675V (6.4%, 6/94 infections), previously not observed, rather than continued expansion of 561H (23.5% 20/85). Mutations to partner drugs and other anti-malarials were variable, with high levels of multidrug resistance 1 (mdr1) N86 (95.5%) associated with lumefantrine decreased susceptibility and dihydrofolate reductase (dhfr) 164L (24.7%) associated with a high level of antifolate resistance, but low levels of amodiaquine resistance polymorphisms with chloroquine resistance transporter (crt) 76T: at 6.1% prevalence. No hrp2 or hrp3 gene deletions associated with diagnostic resistance were found. Conclusions Increasing prevalence of artemisinin partial resistance due to k13-561H and the rapid expansion of k13-675V is concerning for the longevity of artemisinin effectiveness in the region. False negative RDT results do not appear to be an issue with no hrp2 or hpr3 deletions detected. Continued molecular surveillance in this region and surrounding areas is needed to follow artemisinin partial resistance and provide early detection of partner drug resistance, which would likely compromise control and increase malaria morbidity and mortality in East Africa.

Abstract Introduction Acute kidney injury (AKI) is associated with increased risk of heart failure (HF). Determining the type of HF experienced by AKI survivors (heart failure with preserved or reduced ejection fraction, HFpEF or HFrEF) could suggest potential mechanisms underlying the association and opportunities for improving post-AKI care. Methods In this retrospective study of adults within the Vanderbilt University health system with a diagnosis of HF, we tested whether AKI events in the two years preceding incident HF associated more with HFpEF or HFrEF while controlling for known predictors. HF outcomes were defined by administrative codes and classified as HFpEF or HFrEF by echocardiogram data. We used multivariable logistic regression models to estimate the effects of AKI on the odds of incident HFpEF versus HFrEF. Results AKI (all stages) trended towards a preferential association with HFpEF in adjusted analyses (adjusted OR 0.80, 95% CI 0.63 – 1.01). Stage 1 AKI was associated with higher odds of HFpEF that was statistically significant (adjusted OR 0.62, 95% CI 0.43 – 0.88), whereas stages 2–3 AKI showed a trend toward HFrEF that did not reach statistical significance (adjusted OR 1.11, 95% CI 0.76 – 1.63). Conclusions AKI as a binary outcome trended towards a preferential association with HFpEF. Stage 1 AKI was associated with higher odds of HFpEF, whereas stage 2–3 trended towards an association with HFrEF that did not meet statistical significance. Different mechanisms may predominate in incident HF following mild versus more severe AKI. Close follow-up with particular attention to volume status and cardiac function after discharge is warranted after even mild AKI.

Abstract Background Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer death among women globally. Despite advances, there is considerable variation in clinical outcomes for patients with non-luminal A tumors, classified as difficult-to-treat breast cancers (DTBC). This study aims to delineate the proteogenomic landscape of DTBC tumors compared to luminal A (LumA) tumors. Methods We retrospectively collected a total of 117 untreated primary breast tumor specimens, focusing on DTBC subtypes. Breast tumors were processed by laser microdissection (LMD) to enrich tumor cells. DNA, RNA, and protein were simultaneously extracted from each tumor preparation, followed by whole genome sequencing, paired-end RNA sequencing, global proteomics and phosphoproteomics. Differential feature analysis, pathway analysis and survival analysis were performed to better understand DTBC and investigate biomarkers. Results We observed distinct variations in gene mutations, structural variations, and chromosomal alterations between DTBC and LumA breast tumors. DTBC tumors predominantly had more mutations in TP53, PLXNB3, Zinc finger genes, and fewer mutations in SDC2, CDH1, PIK3CA, SVIL, and PTEN. Notably, Cytoband 1q21, which contains numerous cell proliferation-related genes, was significantly amplified in the DTBC tumors. LMD successfully minimized stromal components and increased RNA–protein concordance, as evidenced by stromal score comparisons and proteomic analysis. Distinct DTBC and LumA-enriched clusters were observed by proteomic and phosphoproteomic clustering analysis, some with survival differences. Phosphoproteomics identified two distinct phosphoproteomic profiles for high relapse-risk and low relapse-risk basal-like tumors, involving several genes known to be associated with breast cancer oncogenesis and progression, including KIAA1522, DCK, FOXO3, MYO9B, ARID1A, EPRS, ZC3HAV1, and RBM14. Lastly, an integrated pathway analysis of multi-omics data highlighted a robust enrichment of proliferation pathways in DTBC tumors. Conclusions This study provides an integrated proteogenomic characterization of DTBC vs LumA with tumor cells enriched through laser microdissection. We identified many common features of DTBC tumors and the phosphopeptides that could serve as potential biomarkers for high/low relapse-risk basal-like BC and possibly guide treatment selections.

Abstract Background Inflammatory bowel disease (IBD) affects over 3 million Americans and has a relapsing and remitting course with up to 30% of patients experiencing exacerbations each year despite the availability of immune targeted therapies. An urgent need exists to develop adjunctive treatment approaches to better manage IBD symptoms and disease activity. Circadian disruption is associated with increased disease activity and may be an important modifiable treatment target for IBD. Morning light treatment, which advances and stabilizes circadian timing, may have the potential to improve IBD symptoms and disease activity, but no studies have explored these potential therapeutic benefits in IBD. Therefore, in this study, we aim to test the effectiveness of morning light treatment for patients with IBD. Methods We will recruit sixty-eight individuals with biopsy-proven IBD and clinical symptoms and randomize them to 4-weeks of morning light treatment or 4-weeks of treatment as usual (TAU), with equivalent study contact. Patient-reported outcomes (IBD-related quality of life, mood, sleep), clinician-rated disease severity, and a biomarker of gastrointestinal inflammation (fecal calprotectin) will be assessed before and after treatment. Our primary objective will be to test the effect of morning light treatment versus TAU on IBD-related quality of life and our secondary objectives will be to test the effects on clinician-rated disease activity, depression, and sleep quality. We will also explore the effect of morning light treatment versus TAU on a biomarker of gastrointestinal inflammation (fecal calprotectin), and the potential moderating effects of steroid use, restless leg syndrome, and biological sex. Discussion Morning light treatment may be an acceptable, feasible, and effective adjunctive treatment for individuals with active IBD suffering from impaired health-related quality of life. Trial registration The study protocol was registered on ClinicalTrials.gov as NCT06094608 on October 23, 2023, before recruitment began on February 1, 2024.

Abstract Background Total knee arthroplasty (TKA) is a successful treatment for end-stage osteoarthritis, yet some patients still experience postoperative pain. Genicular nerve radiofrequency ablation (GNRFA) has become a potential modality to address pain in TKA. This systematic review aims to critically analyze the applicability of GNRFA in perioperative pain control prior to TKA, as well as a treatment modality for chronic painful well-appearing TKA. Methods PubMed, Medline, EMBASE, Google Scholar, Scopus, and COCHRANE databases, as well as the ClinicalTrials.gov register, were reviewed. The search included randomized controlled trials and cohort studies. The sample population focused on two cohorts; those who underwent TKA and utilized intentional GNRFA as a perioperative pain control modality, and those utilizing the treatment modality for chronic pain in well-appearing TKA. GNRFA was the intervention studied, and postoperative outcomes were compared with the control group, which consisted of those not receiving GNRFA. Result Eight total publications were identified as relevant to this search. Among the pre-TKA studies, there was variability in results; these inconsistencies were attributed to a lack of standardization, especially with regard to type, timing, and targeted nerves with ablation. Likewise, while the results were improved among the population with chronic painful TKA receiving GNRFA, these inconsistencies still existed. Conclusions Current evidence suggests GNRFA as a possible pre-TKA intervention to potentially minimize opioid consumption, patient-reported pain, length of stay, and increased range of motion and activity. However, the short-lived duration in the setting of chronically painful well-appearing TKA represents a major barrier that warrants further investigation. Limitations include small sample size, heterogeneity, lack of standardization of techniques among studies, and lack of direct comparison and meta-analysis. Further research should focus on the standardization of technique as well as analyzing various patient and health-system-related factors that correlate with sustained positive outcomes.

Abstract Introduction Peritoneal dialysis (PD) is an effective renal replacement modality in people with HIV (PWH) with end-stage kidney disease (ESKD), particularly those with residual kidney function. Data on pharmacokinetics (PK) of antiretrovirals in patients on peritoneal dialysis are limited. Methods A single-participant study was performed on a 49-year-old gentleman with ESKD on PD and controlled HIV on once daily dolutegravir (DTG) 50 mg + tenofovir alafenamide (TAF) 25 mg / emtricitabine (FTC) 200 mg. He underwent serial blood plasma, peripheral blood mononuclear cell, and urine PK measurements over 24 h after an observed DTG + FTC/TAF dose. Results Plasma trough (Cmin) concentrations of TAF, tenofovir (TFV), FTC, and DTG were 0.05, 164, 1,006, and 718 ng/mL, respectively. Intracellular trough concentrations of TFV-DP and FTC-TP were 1142 and 11,201 fmol/million cells, respectively. Compared to published mean trough concentrations in PWH with normal kidney function, observed TFV and FTC trough concentrations were 15.5- and 20-fold higher, while intracellular trough concentrations of TFV-DP and FTC-TP were 2.2-fold and 5.4-fold higher, respectively. TFV and FTC urine levels were 20 times lower than in people with normal GFR. Conclusions In a single ESKD PWH on PD, daily TAF was associated with plasma TFV and intracellular TFV-DP trough concentrations 15-fold and 2-fold higher than those of people with uncompromised kidney function, potentially contributing to nephrotoxicity. This suggests that TFV accumulates on PD; thus, daily TAF in PD patients may require dose adjustment or regimen change to optimize treatment, minimize toxicity, and preserve residual kidney function.

Abstract Background Patients with rheumatoid arthritis (RA) are at risk of developing interstitial lung disease (ILD), which is associated with high mortality. Screening tools based on risk factors are needed to decide which patients with RA should be screened for ILD using high-resolution computed tomography (HRCT). The ANCHOR-RA study is a multi-national cross-sectional study that will develop a multivariable model for prediction of RA-ILD, which can be used to inform screening for RA-ILD in clinical practice. Methods Investigators will enrol consecutive patients with RA who have ≥ 2 of the following risk factors for RA-ILD: male; current or previous smoker; age ≥ 60 years at RA diagnosis; high-positive rheumatoid factor and/or anti-cyclic citrullinated peptide (titre > 3 x upper limit of normal); presence or history of certain extra-articular manifestations of RA (vasculitis, Felty’s syndrome, secondary Sjögren’s syndrome, cutaneous rheumatoid nodules, serositis, and/or scleritis/uveitis); high RA disease activity in the prior 12 months. Patients previously identified as having ILD, or who have had a CT scan in the prior 2 years, will not be eligible. Participants will undergo an HRCT scan at their local site, which will be assessed centrally by two expert radiologists. Data will be collected prospectively on demographic and RA-related characteristics, patient-reported outcomes, comorbidities and pulmonary function. The primary outcomes will be the development of a probability score for RA-ILD, based on a multivariable model incorporating potential risk factors commonly assessed in clinical practice, and an estimate of the prevalence of RA-ILD in the study population. It is planned that 1200 participants will be enrolled at approximately 30 sites in the USA, UK, Germany, France, Italy, Spain. Discussion Data from the ANCHOR-RA study will add to the body of evidence to support recommendations for screening for RA-ILD to improve detection of this important complication of RA and enable early intervention. Trial registration clinicaltrials.gov NCT05855109 (submission date: 3 May 2023).

Abstract Oxide semimetals exhibiting both nontrivial topological characteristics stand as exemplary parent compounds and multiple degrees of freedom, offering a promise for the realization of novel electronic states. In this work, we report the structural and transport phase transition in an oxide semimetal, SrNbO3, achieved through effective anion doping. Notably, the resistivity increased by more than three orders of magnitude at room temperature upon nitrogen‐doping. The extent of electronic modulation in SrNbO3 is strongly correlated with misfit strain, underscoring its phase instability to both chemical doping and crystallographic symmetry variations. Using first‐principles calculations, we discern that elevating the level of nitrogen doping induces an upward shift in the conductive bands of SrNbO3−δNδ. Consequently, a transition from a metallic state to an insulating state becomes apparent as the nitrogen concentration reaches a threshold of 1/3. This investigation shows effective anion engineering in oxide semimetals, offering pathways for manipulating their physical properties.

Qubit decoherence unavoidably degrades the fidelity of quantum logic gates. Accordingly, realizing gates that are as fast as possible is a guiding principle for qubit control, necessitating protocols for mitigating error channels that become significant as gate time is decreased. One such error channel arises from the counter-rotating component of strong, linearly polarized drives. This error channel is particularly important when gate times approach the qubit Larmor period and represents the dominant source of infidelity for sufficiently fast single-qubit gates with low-frequency qubits such as fluxonium. In this work, we develop and demonstrate two complementary protocols for mitigating this error channel. The first protocol realizes circularly polarized driving in circuit QED through simultaneous charge and flux control. The second protocol—commensurate pulses—leverages the coherent and periodic nature of counter-rotating fields to regularize their contributions to gates, enabling single-qubit gate fidelities reliably exceeding 99.997%. This protocol is platform independent and requires no additional calibration overhead. This work establishes straightforward strategies for mitigating counter-rotating effects from strong drives in circuit QED and other platforms, which we expect to be helpful in the effort to realize high-fidelity control for fault-tolerant quantum computing.

Autism Spectrum Disorders (ASD) encompass a wide array of debilitating symptoms, including severe sensory deficits and abnormal language development. Sensory deficits early in development may lead to broader symptomatology in adolescents and adults. The mechanistic links between ASD risk genes, sensory processing and language impairment are unclear. There is also a sex bias in ASD diagnosis and symptomatology. The current study aims to identify the developmental trajectory and genotype- and sex-dependent differences in auditory sensitivity and temporal processing in a Pten-deletion (phosphatase and tensin homolog missing on chromosome 10) mouse model of ASD. Auditory temporal processing is crucial for speech recognition and language development and deficits will cause language impairments. However, very little is known about the development of temporal processing in ASD animal models, and if there are sex differences. To address this major gap, we recorded epidural electroencephalography (EEG) signals from the frontal (FC) and auditory (AC) cortex in developing and adult Nse-cre PTEN mice, in which Pten is deleted in specific cortical layers (layers III-V) (PTEN conditional knock-out (cKO). We quantified resting EEG spectral power distribution, auditory event related potentials (ERP) and temporal processing from awake and freely moving male and female mice. Temporal processing is measured using a gap-in-noise-ASSR (auditory steady state response) stimulus paradigm. The experimental manipulation of gap duration and modulation depth allows us to measure cortical entrainment to rapid gaps in sounds. Temporal processing was quantified using inter-trial phase clustering (ITPC) values that account for phase consistency across trials. The results show genotype differences in resting power distribution in PTEN cKO mice throughout development. Male and female cKO mice have significantly increased beta power but decreased high frequency oscillations in the AC and FC. Both male and female PTEN cKO mice show diminished ITPC in their gap-ASSR responses in the AC and FC compared to control mice. Overall, deficits become more prominent in adult (p60) mice, with cKO mice having significantly increased sound evoked power and decreased ITPC compared to controls. While both male and female cKO mice demonstrated severe temporal processing deficits across development, female cKO mice showed increased hypersensitivity compared to males, reflected as increased N1 and P2 amplitudes. These data identify a number of novel sensory processing deficits in a PTEN-ASD mouse model that are present from an early age. Abnormal temporal processing and hypersensitive responses may contribute to abnormal development of language function in ASD.

Abstract. Background:. Lumbar facet joint arthropathy (LFJA) is a major cause of low back pain (LBP), with current treatments offering limited long-term benefits. Bone marrow–derived mesenchymal stem cells (BM-MSCs) show promise due to their immunomodulatory and trophic effects, potentially addressing underlying degenerative processes in LFJA. Objectives:. This initial report describes the outcomes of the first treated patient in an ongoing mutidisciplinary phase 1 clinical trial evaluating the safety and feasibility of intra-articular allogeneic BM-MSCs for painful LFJA. Methods:. Following enrollment in our IRB-approved protocol, symptomatic LFJA was confirmed through double blocks on L4 and L5 medial branches. Two 1-mL syringes, each containing 10 million BM-MSCs, were prepared in the cGMP facility and administered bilaterally to the patient’s L4-L5 lumbar facet joints. The patient underwent standardized follow-ups, including clinical examinations and functional and imaging assessments for 2 years, utilizing patient-reported outcomes measurement information system—computer adaptive tests (PROMIS CATs), visual analogue scale, Oswestry disability index, work functional status and opioid pain medication use, and MR imaging Fenton–Czervionke score. Results:. The patient tolerated the procedure well, with no drug-related adverse events during the study period. Pain, spine function, and work functional status improved at multiple follow-ups. This patient also reported improvements in mental and social health, along with a notable improvement in the grade of facet synovitis observed at the one-year follow-up MRI evaluation. Conclusions:. This case report suggests the safety and feasibility of administering intra-articular allogeneic BM-MSCs, offering therapeutic benefits for pain management and functional activities.

Most malaria rapid diagnostic tests (RDTs) detect Plasmodium falciparum histidine-rich protein 2 (PfHRP2) and PfHRP3, but deletions of pfhrp2 and phfrp3 genes make parasites undetectable by RDTs. We analyzed 19,313 public whole-genome-sequenced P. falciparum field samples to understand these deletions better. Pfhrp2 deletion only occurred by chromosomal breakage with subsequent telomere healing. Pfhrp3 deletions involved loss from pfhrp3 to the telomere and showed three patterns: no other associated rearrangement with evidence of telomere healing at breakpoint (Asia; Pattern 13-TARE1); associated with duplication of a chromosome 5 segment containing multidrug-resistant-1 gene (Asia; Pattern 13-5++); and most commonly, associated with duplication of a chromosome 11 segment (Americas/Africa; Pattern 13-11++). We confirmed a 13–11 hybrid chromosome with long-read sequencing, consistent with a translocation product arising from recombination between large interchromosomal ribosome-containing segmental duplications. Within most 13-11++ parasites, the duplicated chromosome 11 segments were identical. Across parasites, multiple distinct haplotype groupings were consistent with emergence due to clonal expansion of progeny from intrastrain meiotic recombination. Together, these observations suggest negative selection normally removes 13-11++pfhrp3 deletions, and specific conditions are needed for their emergence and spread including low transmission, findings that can help refine surveillance strategies.

Summary: Background: Interstitial lung disease (ILD) poses a serious threat in patients with rheumatoid arthritis (RA). However, the impact of cornerstone drugs, including methotrexate (MTX) and TNF inhibitor, on RA-associated ILD (RA-ILD) remains controversial. Methods: Using an SKG mouse model and single-cell transcriptomics, we investigated the effects of MTX and TNF blockade on ILD. Findings: Our study revealed that MTX exacerbates pulmonary inflammation by promoting immune cell infiltration, Th17 activation, and fibrosis. In contrast, TNF inhibitor ameliorates these features and inhibits ILD progression. Analysis of data from a human RA-ILD cohort revealed that patients with ILD progression had persistently higher systemic inflammation than those without progression, particularly among the subgroup undergoing MTX treatment. Interpretation: These findings highlight the need for personalized therapeutic approaches in RA-ILD, given the divergent outcomes of MTX and TNF inhibitor. Funding: This work was funded by GENINUS Inc., and the National Research Foundation of Korea, and Seoul National University Hospital.

BackgroundHIV continues to have a disproportionate impact on specific populations in Malaysia, particularly men who have sex with men (MSM). HIV self-testing (HIVST) is a strategy that has been shown to scale up HIV testing rates. However, it faces shortcomings because of concerns about self-efficacy, result interpretation, and lack of counseling and linkage to care. This underscores the need for an innovative approach that integrates HIVST with timely counseling, expert guidance, and referrals to enhance engagement in relevant HIV prevention or treatment. ObjectiveThis study aims to describe the protocol used in developing and testing a web-based platform (ie, CINTAI) providing an HIVST kit and real-time e-counseling to support online-to-offline linkage to HIV care services for MSM in Malaysia. MethodsThe methods are reported according to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 guidelines. In phase I, we will adapt existing HIVST web-based platforms to create a new online-to-offline HIVST and counseling platform called “CINTAI” for Malaysian MSM. In phase II, we will use a type 1 hybrid implementation trial design to determine the feasibility, acceptability, and preliminary efficacy of “CINTAI” compared with treatment as usual among Malaysian MSM, with assessments conducted over 6 months. Multilevel implementation factors will also be collected to guide future adoption and scale-up. We will enroll 78 MSM in the pilot randomized controlled trial. Baseline characteristics will be tested for homogeneity between groups using appropriate statistical tests. A generalized linear mixed model with random subject effects will account for within-subject correlation. Treatment assignment, time, interaction, and confounders will be included. The proportion of MSM tested for HIV over 6 months and other outcomes (pre-exposure prophylaxis for HIV or antiretroviral therapy linkage, HIV risk behaviors, and chemsex harm reduction) will be compared using linear contrasts. ResultsWe completed phase I of the proposed study in April 2024 and started phase II in May 2024, with 15 participants recruited (7 in the CINTAI and 8 in the treatment-as-usual groups). On the basis of a series of formative works completed during phase I, we developed a fully functional, web-based platform that provides a digital platform for MSM in Malaysia to order HIVST kits for free and to receive HIV counseling, followed by offline linkage to HIV prevention services (if HIV negative) or HIV treatment services (if HIV positive). ConclusionsDespite being at high risk for HIV transmission, MSM in Malaysia have alarmingly low testing and linkage to HIV care services, prompting the need for innovative approaches to support HIV prevention efforts. If found to be feasible and acceptable, CINTAI can be easily adapted for a range of health outcomes and health care delivery services for MSM, including adaptation to other low- and middle-income countries. International Registered Report Identifier (IRRID)DERR1-10.2196/60962

Background: Periprosthetic fractures (PPFs) after total joint arthroplasty (TJA) can be devastating, yet their long-term impact has not been well described. The aim of this study is to compare the long-term outcomes of patients who sustained a PPF about a TJA with those of patients who underwent an uncomplicated TJA. Methods: Patients who sustained a PPF after primary TJA between 2005 and 2014 were identified. Seventeen patients with a minimum 2-year follow-up (PPF cohort) were compared to a matched cohort of 67 patients who underwent uncomplicated TJA. Demographic data, comorbidities, surgical details, and complications were analyzed. Quality of life and functional outcomes were assessed with 12-Item Short Form Health Survey (SF-12), Western Ontario and McMasdter Universities Arthritis Index (WOMAC), and Knee Society Function Score. Results: The overall complication rate was 41.2% in the PPF group, including 3 additional fractures (17.6%), 2 wound infections (11.8%), one prosthetic joint infection (5.8%), and one painful patellar hardware necessitating removal (5.8%). At 2 years, both physical and mental components of the SF-12 were significantly lower for the PPF cohort vs control (SF-12-P, 28.7 ± 4.4 vs 40.8 ± 10.3, P < .001, SF-12-M, 36.7 ± 5.07 vs 55.0 ± 8.19, P < .0001). WOMAC pain and function scores were also significantly worse in the PPF cohort vs control at 2 years (WOMAC-pain, 38.8 ± 29.9 vs 87.4 ± 22.1; P < .0001, WOMAC-function, 40.7 ± 8.7 vs 76.1 ± 20.3; P < .0001). At 2 years, score improvements from prearthroplasty baseline were significantly greater in the control cohort vs PPF for SF-12-physical, WOMAC-pain, and WOMAC-function. Conclusions: Patients who sustained PPFs following TJA have poor long-term outcomes despite appropriate treatment. These results can help counsel patients and encourage heightened efforts to minimize the risk of PPF. Level of Evidence: Level III.