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Repressor elements significantly influence economically relevant phenotypes in pigs; however, their precise roles and characteristics are inadequately understood. In the present study, we employed H3K27me3 profiling, assay for transposase-accessible chromatin with highthroughput sequencing (ATAC-seq), and RNA sequencing (RNA-seq) data across six tissues derived from three embryonic layers to identify and map 2 034 super repressor elements (SREs) and 22 223 typical repressor elements (TREs) in the pig genome. Notably, many repressor elements were conserved across mesodermal and ectodermal tissues. SREs exhibited tight regulation of their target genes, affecting a limited number of genes within a specific genomic region with pronounced effects, while TREs exerted broader but weaker regulation over a wider range of target genes. Furthermore, in neuronal tissues, genes regulated by repressor elements started to be repressed during the differentiation of stem cells into progenitor cells. Notably, analysis showed that many repressor elements exhibited cooperative and additive effects on the modulation of KLF4 expression. This research provides the first comprehensive map of pig repressor elements, serving as an essential reference for future studies on repressor elements.

The present study proposes the development of new wine recognition models based on Artificial Intelligence (AI) applied to the mid-level data fusion of 1 H NMR and Raman data. In this regard, a supervised machine learning method, namely Support Vector Machines (SVMs), was applied for classifying wine samples with respect to the cultivar, vintage, and geographical origin. Because the association between the two data sources generated an input space with a high dimensionality, a feature selection algorithm was employed to identify the most relevant discriminant markers for each wine classification criterion, before SVM modeling. The proposed data processing strategy allowed the classification of the wine sample set with accuracies up to 100% in both cross-validation and on an independent test set and highlighted the efficiency of 1 H NMR and Raman data fusion as opposed to the use of a single-source data for differentiating wine concerning the cultivar and vintage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

The proportions of carbon (C), nitrogen (N), and phosphorus (P) in surface ocean particulate matter deviate greatly from the canonical Redfield Ratio (C:N:P = 106:16:1) in space and time with significant implications for global carbon storage as this matter reaches the deep ocean. Recent work has revealed clear latitudinal patterns in C:N:P, yet the relative importance of ecological, physiological, or biochemical processes in creating these patterns is unclear. We present high-resolution, concurrent measurements of particulate C:N:P, macromolecular composition, environmental conditions, and plankton community composition from a transect spanning a subtropical-subpolar boundary, the North Pacific Transition Zone. We find that the summed contribution of macromolecules to particulate C, N, and P is consistent with, and provides interpretation for, particulate C:N:P patterns. A decline in particulate C:N from the subtropical to subpolar North Pacific largely reflects an increase in the relative contribution of protein compared to carbohydrate and lipid, whereas variation in C:P and N:P correspond to shifts in protein relative to polyphosphate, DNA, and RNA. Possible causes for the corresponding trends in C:N and macromolecular composition include physiological responses and changes in community structure of phytoplankton, which represented approximately 1/3 rd of particulate C across the transect. Comparison with culture experiments and an allocation-based model of phytoplankton macromolecular composition suggest that physiological acclimation to changing nutrient supply is the most likely explanation for the latitudinal trend in C:N, offering both a mechanistic interpretation and biochemical basis for large-scale patterns in C:N:P., Competing Interests: Competing interests statement:The authors declare no competing interest.

Evaluating the steady-state protein level of the EGFR in live cells presents significant challenges compared to measuring its kinase activity. Traditional testing methods, such as immunoblotting, ELISA, and immunofluorescence assays, are generally restricted to fixed cells or cell lysates. Despite their utility, these methods are cumbersome and provide only intermittent snapshots of EGFR levels at specific time points. With emerging trends in drug development shifting toward engineering novel agents that promote protein degradation, rather than simply inhibiting kinase activity, a tool that enables real-time, quantitative detection of drug effects in live cells could catalyze advances in the field. Such an innovation would expedite the drug development process, enhancing the translation of research findings into effective, patient-centered therapies. The NanoLuc-EGFR cell line, created through CRISPR genome editing, allows for the continuous tracking and analysis of EGFR protein levels and their degradation within live cells. This approach provides quantitative monitoring of protein dynamics in real time, offering insights that go beyond absolute protein levels to include aspects such as protein stability and degradation rate. Using this cell line model, we observed that AT13387 and H84T BanLec induce EGFR degradation in A549-HiBiT cells, with the results confirmed by immunoblotting. In contrast, Erlotinib, Osimertinib, and Cetuximab inhibit EGFR phosphorylation without altering total EGFR levels, as validated by the HiBiT luciferase assay. The NanoLuc-EGFR cell line marks a significant advancement in understanding protein regulation and serves as an instrumental platform for investigating targeted therapies that modulate protein kinases, especially those that induce protein degradation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The chemiluminescent light-emission pathway of phenoxy-1,2-dioxetane luminophores attracts growing interest within the scientific community. Dioxetane probes undergoing rapid flash-type chemiexcitation exhibit higher detection sensitivity than those with a slow glow-type chemiexcitation rate. We discovered that dioxetanes fused to non-strained six-member rings, with hetero atoms or inductive electron-withdrawing groups, present both accelerated chemiexcitation rates and elevated chemical stability compared to dioxetanes fused to four-member strained rings. DFT computational simulations supported the chemiexcitation acceleration observed by spiro-fused six-member rings with inductive electron-withdrawing groups of dioxetanes. Specifically, a spiro-dioxetane with a six-member sulfone ring exhibited a chemiexcitation rate 293-fold faster than that of spiro-adamantyl-dioxetane. A turn-ON dioxetane probe for the detection of the enzyme β-galactosidase, containing the six-member sulfone unit, exhibited a S/N value of 108 in LB cell growth medium. This probe demonstrated a substantial increase in detection sensitivity towards E. coli bacterial cells expressing β-galactosidase, with an LOD value that is 44-fold more sensitive than that obtained by the adamantyl counterpart. The accelerated chemiexcitation and the elevated chemical stability presented by dioxetane containing a spiro-fused six-member ring with a sulfone inductive electron-withdrawing group, make it an ideal candidate for designing efficient turn-on chemiluminescent probes with exceptionally high detection sensitivity., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Many individually randomized group treatment (IRGT) trials randomly assign individuals to study arms but deliver treatments via shared agents, such as therapists, surgeons, or trainers. Post-randomization interactions induce correlations in outcome measures between participants sharing the same agent. Agents can be nested in or crossed with trial arm, and participants may interact with a single agent or with multiple agents. These complications have led to ambiguity in choice of models but there have been no systematic efforts to identify appropriate analytic models for these study designs. To address this gap, we undertook a simulation study to examine the performance of candidate analytic models in the presence of complex clustering arising from multiple membership, single membership, and single agent settings, in both nested and crossed designs and for a continuous outcome. With nested designs, substantial type I error rate inflation was observed when analytic models did not account for multiple membership and when analytic model weights characterizing the association with multiple agents did not match the data generating mechanism. Conversely, analytic models for crossed designs generally maintained nominal type I error rates unless there was notable imbalance in the number of participants that interact with each agent., (© 2024 The Author(s). Statistics in Medicine published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Aryl hydantoins were identified in the early 1980s as a promising antischistosomal chemotype. However, as exemplified by Ro 13-3978, this compound series produced antiandrogenic side effects on the host, a not unexpected outcome given their structural similarity to the antiandrogenic drug nilutamide. The two key advances in our optimization of Ro 13-3978 were swapping the aryl trifluoromethyl substituent with a difluoroethyl to abolish antiandrogenic effects and replacing the hydrogen atoms of the gem -dimethyl substructure with deuterium atoms to increase metabolic stability. Combining these two structural changes led to the discovery of single-dose drug candidate AR102, a compound with potent, selective, and broad-spectrum activity against schistosomes, a long pharmacokinetic half-life in preclinical species, and an acceptable safety profile.

This study investigates the band inversion of flat bands in zig-zag graphene nanoribbons (ZGNRs) using a tight-binding model. The band inversion results from symmetry breaking in the transverse direction, achievable through deposition on specific substrates such as separated silicon carbide or hexagonal boron nitride sheets. Upon band inversion, ZGNRs exhibit electronic structures characterized by valley degeneracy and band gap properties, which can be modulated by transverse electric fields. To explore the impact of this level degeneracy on thermoelectric properties, we employ Green's function techniques to calculate thermoelectric quantities in ZGNR segments with staggered sublattice potentials and transverse electric fields. Two carrier transport scenarios are considered: the chemical potential is positioned above and below the highest occupied molecular orbital. We analyze thermionic-assisted transport (TAT) and direct ballistic transport (DBT). Level degeneracy enhances the electric power factors of ZGNRs by increasing electrical conductance, while the Seebeck coefficient remains robust in the TAT scenario. Conversely, in DBT, the enhancement of the power factor primarily stems from improvements in the Seebeck coefficient at elevated temperatures.

Introduction: Remission rates for ulcerative colitis (UC) remain low despite significant progress in disease understanding and the introduction of novel therapeutic agents. Several challenges contribute to this, including the heterogeneity of the disease, suboptimal efficacy of current diagnostic and therapeutic tools, drug safety concerns, and limited access to newer treatment options., Areas Covered: This review evaluates current treatment targets in UC, assessing the effectiveness of various therapies and management strategies in achieving remission. We explore the potential role of personalized medicine, which tailors treatment based on clinical predictors, genetic factors, and immunologic profiles. Personalized approaches show promise in improving remission rates by addressing the unique characteristics of each patient. We also discussed the feasibility of adapting such management models and suggested solutions to some of the challenges in their implementation., Expert Opinion: Future efforts should prioritize the continued development of biologics, small molecules, and digital health solutions, alongside noninvasive monitoring techniques. These innovations could not only enhance patient outcomes by improving remission rates but also reduce healthcare costs by minimizing hospitalization and surgical interventions. Ultimately, a personalized, stratified approach to UC management is key to optimizing patient care and addressing the unmet needs in this field.

Background and Purpose: There has been a distinction made in the 2001 Canadian C-Spine Rule regarding patients 65 and older and younger than 65 years of age as far as indications for cervical spine CT scanning. We sought to determine if there are differences in the symptoms, mechanisms of injury, fracture locations, and types that are still relevant in 2024., Materials and Methods: The institutional review board approved this retrospective study of cervical spine CT emergency department results from 2 hospitals in our health system after reviewing 5 years of data in patients experiencing trauma. In addition to the primary variable of age (younger than 65 years and 65 years and older), we looked at injury mechanism, fracture types, sites, symptoms, and operative or medical treatments. Because the demographics of our home site is different from most towns in the United States, we provide race/ethnicity data., Results: Of 21,986 cervical spine CTs, 190/9455 (2.0%) participants 65 years of age and older and 199/12,531 (1.6%) participants younger than 65 years of age had fractures (total, 389/21,986, 1.8%). There were more cases of falls from standing (106, 55.8%) and falls from a height (46, 4.2%) in those 65 years and older and this mechanism was associated with a higher risk of C1 and C2 fractures (52, 27.4%; and 78, 41.1%, respectively). Among the C1 fractures, anterior and posterior arch fractures predominated (37, 19.5%). For C2 fractures, types 2 and 3 odontoid fractures (39, 20.5%; and 12, 6.3%) were more common in the older cohort. Motor vehicle collisions were more common in the younger cohort (89, 44.7%), and they were associated with more C5-C7 fractures (47, 23.6%; 60, 30.2%; and 66, 33.2%, respectively) including the facets (49, 24.6%), spinous processes (31, 15.6%), and transverse processes (52, 26.1%). Overall, the rates of instability, surgical intervention, and asymptomatic fractures were similar in the 2 age groups., Conclusions: Cervical spine fractures appear in about 1.8% of the CT scans performed in a busy emergency department environment. Fractures in the elderly occur more commonly due to falls, are located at C1 and C2, and may involve ligamentous injuries. Younger patients incur trauma more commonly due to motor vehicle collisions, and they are more likely to affect the posterior elements, especially C5-C7. The differences in trends for fractures in the 65 years of age and older and younger than 65 years of age groups have persisted since the Canadian C-Spine Rule 1996-1998 data were collected., (© 2024 by American Journal of Neuroradiology.)

Abstract: Asciminib is a myristoyl site BCR::ABL1 inhibitor approved for patients with chronic-phase chronic myeloid leukemia (CP-CML) failing ≥2 prior lines of therapy. The Australasian Leukaemia and Lymphoma Group conducted the Asciminib Evaluation in Newly Diagnosed CML study to assess efficacy of asciminib for newly diagnosed CP-CML. Patients commenced asciminib 40 mg twice daily. Patients with treatment failure, defined as BCR::ABL1 of >10% at 3 or 6 months, or >1% at 12 or 18 months, received either imatinib, nilotinib, or dasatinib in addition to asciminib. In patients with suboptimal response, defined as levels of 1% to 10% at 6 months, >0.1% to 1% at 12 months, or >0.01% to 1% at 18 months, the asciminib dose was increased to 80 mg twice daily. With a median follow-up of 21 months (range, 0-36), 82 of 101 patients continue asciminib. Most common reasons for treatment discontinuation were adverse events (6%), loss of response (4%), and withdrawn consent (5%). There were no deaths; 1 patient developed lymphoid blast crisis. The coprimary end points were early molecular response (BCR::ABL1 of ≤10% at 3 months), achieved in 93% (96% confidence interval [CI], 86-97%), and major molecular response by 12 months achieved in 79%; (95% CI, 70-87%), respectively. Cumulative incidence of molecular response 4.5 was 53% by 24 months. One patient had 2 cerebrovascular events; no other arterial occlusive events were reported. Asciminib as frontline CP-CML therapy leads to high rates of molecular response with excellent tolerance and a low rate of discontinuation for toxicity. This trial was registered at https://www.anzctr.org.au/ as #ACTRN12620000851965., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Brain AVMs are congenital anomalies of the cerebrovascular system, often discovered incidentally or through symptomatic presentations such as intracranial hemorrhage, seizure, headache, or neurologic deficits. Various treatment modalities exist for AVMs, including radiosurgery, a treatment technique that is noninvasive and efficient. Accurate imaging is crucial for risk assessment, treatment planning, and monitoring of these patients before and after radiosurgery., Purpose: Currently, DSA is the preferred imaging technique. Despite its efficacy, DSA is notably invasive, presenting inherent risks to the patients. This systematic review and meta-analysis aimed to evaluate the efficacy of MRI sequences for monitoring brain AVMs after radiosurgery., Data Source: We performed a comprehensive search of PubMed, Scopus, Web of Science, and EMBASE databases and a methodologic quality assessment with the QUADAS-2 checklist diagnostic test accuracy., Study Selection: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 3,220 abstracts were screened, 98 articles were reviewed in full text, and 14 articles met the inclusion criteria., Data Analysis: We used the bivariate random-effects meta-analysis model with STATA/MP 17 software for data analysis., Data Synthesis: No publication bias was detected. Fourteen studies were eligible for qualitative and quantitative analysis. MRI offers high sensitivity (85%) and specificity (99%) in detecting residual AVMs. Different MRI sequences, including 3D TOF-MRA, 4D MRA, and arterial spin-labeling (ASL) demonstrated varying diagnostic accuracies with areas under the curve of 0.92, 0.97, and 0.96, respectively. 4D MRA had a sensitivity of 72% and specificity of 99%, ASL showed a sensitivity of 90% and specificity of 92%, while 3D TOF-MRA had 90% sensitivity and 87% specificity., Limitations: Meta-regression did not fully explain the sources of heterogeneity. Only 1 study assessed the susceptibility-weighted angiography (SWAN) method, and most studies involved small participant groups with varied MR techniques and sequences. Additionally, the retrospective nature of most studies may introduce bias, warranting cautious interpretation of the results., Conclusions: MRI sequences show acceptable diagnostic performance in postradiosurgery monitoring of brain AVMs, with ASL and 4D MRA showing acceptable diagnostic accuracy. Combining different MRI sequences may further enhance diagnostic reliability. However, further investigation is needed to assess whether MRI sequences can serve as a feasible substitute for DSA, considering their risk-benefit profile, with the potential to establish them as the recommended standard., (© 2025 by American Journal of Neuroradiology.)

Oligodendrocytes (OLs) of the central nervous system require iron for proteolipid biosynthesis during the myelination process. Although most heme is found complexed to hemoglobin in red blood cells, surprisingly, we found that Slc48a1, encoding the heme transporter Hrg1, is expressed at higher levels in OLs than any other cell type in rodent and humans. We confirmed in situ that Hrg1 is expressed in OLs but not their precursors (OPCs) and found that Hrg1 proteins in CNS white matter co-localized within myelin sheaths. In older Hrg1 null mutant mice we observed reduced expression of myelin associated glycoprotein (Mag) and ultrastructural myelin defects reminiscent of Mag-null animals, suggesting myelin adhesion deficiency. Further, we confirmed reduced myelin iron levels in Hrg1 null animals in vivo, and show that OLs in vitro can directly import both the fluorescent heme analogue ZnMP and heme itself, which rescued iron deficiency induced inhibition of OL differentiation in a heme-oxidase-dependent manner. Together these findings indicate OL Hrg1 encodes a functional heme transporter required for myelin integrity., (© 2024 The Author(s). GLIA published by Wiley Periodicals LLC.)

Background: Re-operation after breast-conserving surgery for invasive breast cancer is variable among centres and individual surgeons. In this study, we aimed to characterize the current landscape of practice regarding re-operation for invasive breast cancer in the province of Alberta., Methods: This study was a retrospective review of the Synoptec database for patients undergoing primary breast-conserving surgery for invasive breast cancer or reoperation in the province of Alberta in the year 2020. We extracted data on demographic and tumour characteristics, use of intraoperative margin-assessment strategies, and surgical facility. We conducted univariate and multivariate logistic model analyses., Results: We included 1391 breast surgeries in the study. A total of 158 patients underwent re-operation during the study period. The median time to first reoperation was 34 days. The overall re-operation rate was 11.4% (range 5.4%-18.5%) among surgical facilities. The completion mastectomy rate was 5.2%, and 1.5% of patients underwent multiple revisional surgeries. Tumour multifocality was associated with increased revisional surgery rates on multivariate analysis (odds ratio 2.80)., Conclusion: The results of this study are consistent with the published literature. We have identified heterogeneity among sites in Alberta for revisional surgery after breast-conserving surgery for invasive breast cancer. This highlights an opportunity for ongoing education and quality improvement in breast cancer care in the province of Alberta., Competing Interests: Competing interests:: Lashan Peiris has served as an expert witness in cases of delayed diagnosis of breast cancer for a legal firm in Ontario and has been reimbursed travel expenses to attend a provincial guideline meeting in Alberta. Dr. Peiris is medical lead for the comprehensive breast care program in Edmonton and surgical site lead for the Cross Cancer Institute in Edmonton. No other competing interests were declared., (© 2024 CMA Impact Inc. or its licensors.)

Lithium metal anode batteries have attracted significant attention as a promising energy storage technology, offering a high theoretical specific capacity and a low electrochemical potential. Utilizing lithium metal as the anode material can substantially increase energy density compared with conventional lithium-ion batteries. However, the practical application of lithium metal anodes has encountered notable challenges, primarily due to the formation of dendritic structures during cycling. These dendrites pose safety risks and degrade battery performance. Addressing these challenges necessitates the development of a reliable and effective protection layer for lithium metal. This study presents a cost-effective and convenient method to spontaneously produce lithium metal protective layers by creating polymeric layers by using acrylonitrile (AN). This method remarkably extends 6× of the lifetime of lithium metal anodes under high current density (1 mA/cm 2 ) cycling conditions. While the cycle life of bare lithium metal is approximately 150 h under high current cycling conditions, AN-treated lithium metal anodes exhibit an impressive longevity of over 900 h. The AN-treated lithium metal anodes are further integrated and tested with sulfide-based Li 10 GeP 2 S 12 (LGPS) solid-state electrolytes to evaluate its interfacial stability at a solid-solid interface. The formation of the polyacrylonitrile (PAN)-rich ASEI, due to AN-treatment, effectively reduces and stabilizes the cell overpotential to only one-tenth of that with the interface without treatment. This strategy paves a route to enable a highly efficient and highly stable Li/LGPS solid-state battery interface.

Background: Studying the effect of dietary Spirulina and lysozyme supplementation on the metabolome and proteome of liver tissue contributes to understanding potential hepatic adaptations of piglets to these novel diets. This study aimed to understand the influence of including 10% Spirulina on the metabolome and proteome of piglet liver tissue. Three groups of 10 post-weaned piglets, housed in pairs, were fed for 28 days with one of three experimental diets: a cereal and soybean meal-based diet (Control), a base diet with 10% Spirulina (SP), and an SP diet supplemented with 0.01% lysozyme (SP + L). At the end of the trial, animals were sacrificed and liver tissue was collected. Metabolomics analysis (n = 10) was performed using NMR data analysed with PCA and PLS-DA. Proteomics analysis (n = 5) was conducted using a filter aided sample preparation (FASP) protocol and Tandem Mass Tag (TMT)-based quantitative approach with an Orbitrap mass spectrometer., Results: Growth performance showed an average daily gain reduction of 9.5% and a feed conversion ratio increase of 10.6% in groups fed Spirulina compared to the control group. Metabolomic analysis revealed no significant differences among the groups and identified 60 metabolites in the liver tissue. Proteomics analysis identified 2,560 proteins, with 132, 11, and 52 differentially expressed in the Control vs. SP, Control vs. SP + L and SP vs. SP + L comparisons, respectively. This study demonstrated that Spirulina enhances liver energy conversion efficiency, detoxification and cellular secretion. It improves hepatic metabolic efficiency through alterations in fatty acid oxidation (e.g., upregulation of enzymes like fatty acid synthase and increased acetyl-CoA levels), carbohydrate catabolism (e.g., increased glucose and glucose-6-phosphate), pyruvate metabolism (e.g., higher levels of pyruvate and phosphoenolpyruvate carboxykinase), and cellular defence mechanisms (e.g., upregulation of glutathione and metallothionein). Lysozyme supplementation mitigates some adverse effects of Spirulina, bringing physiological responses closer to control levels. This includes fewer differentially expressed proteins and improved dry matter, organic matter and energy digestibility. Lysozyme also enhances coenzyme availability, skeletal myofibril assembly, actin-mediated cell contraction, tissue regeneration and development through mesenchymal migration and nucleic acid synthesis pathways., Conclusions: While Spirulina inclusion had some adverse effects on growth performance, it also enhanced hepatic metabolic efficiency by improving fatty acid oxidation, carbohydrate catabolism and cellular defence mechanisms. The addition of lysozyme further improved these benefits by reducing some of the negative impacts on growth and enhancing nutrient digestibility, tissue regeneration, and overall metabolic balance. Together, Spirulina and lysozyme demonstrate potential as functional dietary components, but further optimization is needed to fully realize their benefits without compromising growth performance., (© 2024. The Author(s).)

Cardiorenal fibrosis is a common feature of chronic cardiovascular disease and recent data suggests that cytokines and chemokines may also drive fibrosis. Here we tested the hypothesis that CXCR7, a highly conserved chemokine receptor, contributes to cardiac and renal fibrosis. We generated an anti-mouse CXCR7-specific monoclonal antibody (CXCR7 mAb) and tested its anti-fibrotic actions in cardiorenal fibrosis induced using the deoxycorticosterone acetate/uni-nephrectomy (DOCA-UNX) model. CXCR7 mAb treatment (10 mg/kg, twice weekly for 6 weeks) significantly attenuated the development of cardiac and renal fibrosis, and reduced fibrotic and inflammatory gene expression levels, in the absence of an effect on blood pressure. Immunohistochemical analysis demonstrated an increase in the vascular expression of CXCR7 in DOCA-UNX-treated mice. This study demonstrated that a CXCR7 mediated pathway plays a significant role in cardiac and renal fibrosis induced by DOCA-UNX treatment. Accordingly, antagonism of CXCR7 may provide a therapeutic opportunity to mitigate against fibrosis in the setting of mineralocorticoid excess., (© 2024. The Author(s).)

Digital decision support and remote patient monitoring may improve outcomes and efficiency, but rarely scale beyond a single institution. Over the last 5 years, the platform Timely Interventions for Diabetes Excellence (TIDE) has been associated with reduced care provider screen time and improved, equitable type 1 diabetes care and outcomes for 268 patients in a heterogeneous population as part of the Teamwork, Targets, Technology, and Tight Control (4T) Study (NCT03968055, NCT04336969). Previous efforts to deploy TIDE at other institutions continue to face delays. In partnership with the diabetes technology non-profit, Tidepool, we developed Tidepool-TIDE, a clinic-agnostic, turnkey solution available to any clinic in the United States. We present how we overcame common technical and operational barriers specific to scaling digital health technology from one site to many. The concepts described are broadly applicable for institutions interested in facilitating broader adoption of digital technology for population-level management of chronic health conditions., (© 2024. The Author(s).)

Background: Antiretroviral therapy (ART) is recommended for all individuals with HIV infection, including those with acute HIV-1 infection (AHI). While recommendations are similar to those for chronic infection, efficacy data regarding treatment of acute HIV is limited., Methods: This was a single arm, 96-week study of a once-daily integrase inhibitor (INSTI)-based regimen using elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) in AHI. Primary endpoint was proportion of participants with HIV-1 RNA <200 copies/mL and <50 copies/mL by treatment weeks 24 and 48, respectively. We also examined time to viral suppression and weight gain after treatment initiation. Outcomes and characteristics were compared with a historical AHI cohort using a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen with efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF)., Results: Thirty-three participants with AHI were enrolled with 31 available for analyses. Most were African American (61%) and men who have sex with men (73%). Median age was 26 (IQR 22-42). Demographics were similar between the two AHI cohorts. By Week 24, 100% in the INSTI and 99% in the NNRTI cohort were <200 copies/mL; by Week 48, 100% in both cohorts were <50 copies/mL. Time to viral suppression was shorter in the INSTI cohort (median 54 versus 99 days). Mean weight change was similar with a 3.6 kg increase in the INSTI cohort and 2.4 kg in the NNRTI cohort at 96 weeks., Conclusions: INSTI-based ART during AHI resulted in rapid and sustained viral suppression. Over 96 weeks, weight increased in the INSTI-based cohort but was similar to weight increase in a historical NNRTI-based AHI cohort., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background and Purpose: To describe the clinical commissioning of an in-house artificial intelligence (AI) treatment planning platform for head-and-neck (HN) Intensity Modulated Radiation Therapy (IMRT)., Materials and Methods: The AI planning platform has three components: (1) a graphical user interface (GUI) is built within the framework of a commercial treatment planning system (TPS). The GUI allows AI models to run remotely on a designated workstation configured with GPU acceleration. (2) A template plan is automatically prepared involving both clinical and AI considerations, which include contour evaluation, isocenter placement, and beam/collimator jaw placement. (3) A well-orchestrated suite of AI models predicts optimal fluence maps, which are imported into TPS for dose calculation followed by an optional automatic fine-tuning. Six AI models provide flexible tradeoffs in parotid sparing and Planning Target Volume (PTV)-organ-at-risk (OAR) preferences. Planners could examine the plan dose distribution and make further modifications as clinically needed. The performance of the AI plans was compared to the corresponding clinical plans., Results: The average plan generation time including manual operations was 10-15  min per case, with each AI model prediction taking ∼1 s. The six AI plans form a wide range of tradeoff choices between left and right parotids and between PTV and OARs compared with corresponding clinical plans, which correctly reflected their tradeoff designs., Conclusion: The in-house AI IMRT treatment planning platform was developed and is available for clinical use at our institution. The process demonstrates outstanding performance and robustness of the AI platform and provides sufficient validation., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Homeostatic regulation of neuronal activity is essential for robust computation; set-points, such as firing rate, are actively stabilized to compensate for perturbations. The disruption of brain function central to neurodegenerative disease likely arises from impairments of computationally essential set-points. Here, we systematically investigated the effects of tau-mediated neurodegeneration on all known set-points in neuronal activity. We continuously tracked hippocampal neuronal activity across the lifetime of a mouse model of tauopathy. We were unable to detect effects of disease in measures of single-neuron firing activity. By contrast, as tauopathy progressed, there was disruption of network-level neuronal activity, quantified by measuring neuronal pairwise interactions and criticality, a homeostatically controlled, ideal computational regime. Deviations in criticality correlated with symptoms, predicted underlying anatomical pathology, occurred in a sleep-wake-dependent manner, and could be used to reliably classify an animal's genotype. This work illustrates how neurodegeneration may disrupt the computational capacity of neurobiological systems., Competing Interests: Declaration of interests D.M.H. is on the scientific advisory board of C2N diagnostics and has equity. D.M.H. is on the scientific advisory board of Denali Therapeutics, Genentech, and Cajal Therapeutics and consults for Asteroid Therapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale: In patients with obstructive sleep apnea (OSA) treated with continuous positive airway pressure (CPAP), the apnea hypopnea index (AHI) measured off CPAP may be decreased relative to baseline AHI preceding CPAP treatment. Semi-invasive "endo-phenotyping" sleep studies attribute this fall in AHI primarily to improved ventilatory control stability. Phenotyping Using Polysomnography (PUP) attempts to reproduce these studies using routine polysomnography (PSG). Objectives: To determine whether changes in AHI following CPAP associate primarily with changes in PUP-estimated ventilatory control stability (loop gain, LG 1 ) or with changes in other PUP-estimated pathophysiologic mechanisms. Methods: PUP analyses were performed on existing PSGs in research participants who underwent baseline PSG, 4.4±2.2 months CPAP therapy, and CPAP withdrawal with repeat PSG on night 2 of withdrawal. Pre-CPAP PUP-estimated LG 1 , arousal threshold (ArTH), and upper airway collapsibility (Vpassive) and compensation (Vcomp) were compared to corresponding values during CPAP withdrawal. Mixed effects models were constructed to determine which PUP estimate best explained changes in AHI. Results: PSG data were available for 35 participants (age 47±10.8 years; 12 female; BMI 38.5±8.6 kg/m 2 , AHI3A 58.8±33.1 events/hr, 9 mild/moderate OSA, 26 severe OSA). Following CPAP, AHI decreased, but the change was not statistically significant. However, a significant decrease was observed in those with severe OSA (pre-CPAP 68.2 [32.6-86.3] versus CPAP withdrawal 49.0 [36.1-74.4] events/hr). Across all participants, changes in PUP estimates did not exceed test-retest agreement limits. For those with severe OSA, decrease in LG 1 (0.86 [0.61-1.13] pre-CPAP versus 0.71 [0.61-0.99] on CPAP withdrawal) and increase in Vpassive (64.8 [5.4-88.4] %Veupnea pre-CPAP versus 76.4 [20.7-92.7] %Veupnea on CPAP withdrawal) exceeded test-retest agreement limits. Increased Vpassive, decreased LG 1 , and decreased ArTH were predictors of decreased AHI in mixed effects models. Vpassive had the greatest estimated effect on AHI. After accounting for Vpassive, additional estimates did not improve model performance. However, Vpassive and LG 1 were correlated, and post hoc analyses suggest these estimates may be influenced by both upper airway collapsibility and ventilatory control. Conclusions: According to PUP physiologic estimates, decreases in AHI following several months of CPAP therapy are primarily attributable to improved upper airway collapsibility.

Background: Reconstruction of female oncologic peripelvic defects is challenging due to complex anatomy, neoadjuvant chemoradiation, operative resection margins, and wound healing risks. Functional restoration requires thoughtful management focused on defect reconstruction and patient-reported outcomes., Methods: A retrospective chart review of peripelvic reconstruction in female patients at MD Anderson Cancer Center from 2016 to 2023. Data collected included the patient's comorbidities, tumor characteristics, and reconstructive details. Complications were classified as nonoperative or operative within 30 days. Patient outcomes included hernia rates, sexual activity, and revision needs., Results: In the study period, 164 patients underwent peripelvic defect reconstruction. Most had colorectal (57%), anal (17%), or gynecologic malignancies (10%). 83% had prior radiation. 33.3% had Class II or III obesity. The most common resection was open colorectal resection with partial vaginectomy (66%). Pedicled flaps (93%) were frequently used, mainly vertical rectus abdominis muscle (65%) and gracilis (11%). For multi-visceral resections, abdominal-based flaps were used in 95% of open cases and thigh-based flaps in 88.9% of robotic cases. 51% had formal abdominal wall repair. Complications occurred in 47%, with 9.1% needing surgery. Postoperative hernias were reported in 4.9%, with 3% requiring repair. Approximately 11% reported being sexually active at the last follow-up. Of those instructed on vaginal dilator therapy (42%), 24.6% were sexually active., Conclusion: Peri-pelvic soft tissue reconstruction in the oncologic population is safe. Operative complications and hernia rates are low. In robotic surgery, thigh-based flaps are increasingly used to reconstruct the peripelvic region. Return to sexual activity is higher in patients when given dilator therapy instruction., (© 2024 Wiley Periodicals LLC.)

When a household is disconnected from their electric utility service the consequences can be severe, including accumulation of debt, the inability to maintain comfortable temperatures, and in the most extreme cases, homelessness or mortality. While the survey-based literature on utility disconnections has yielded important findings about which households are most likely to experience a utility shutoff, only a few existing studies have used data from utility companies themselves. In this analysis, we utilize zip-code level data from four of California's largest utility providers to measure sociodemographic disparities in disconnections, in addition to the impact of adverse weather. We find that zip codes with a higher share of vulnerable households, especially Black and Hispanic households and households with young children, face a higher number and rate of utility disconnections, even after controlling for an extensive set of factors that are commonly thought to explain higher rates of energy insecurity, including income, housing characteristics, and energy costs. Our analysis also suggests that sociodemographic and weather disparities in disconnections differ between utility types. We conclude by discussing the implications of the findings for research and policy, including the impact of regulation, utility provider practices, and more extreme weather driven by climate change., (© 2024. The Author(s).)

Purpose: Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the targeted AMPA receptor antagonist perampanel on peritumoral hyperexcitability., Experimental Design: An open-label trial was performed comparing perampanel with standard of care (SOC) in patients undergoing resection of newly diagnosed radiologic high-grade glioma. Perampanel was administered as a preoperative loading dose followed by maintenance therapy until progressive disease or up to 12 months. SOC treatment involved levetiracetam for 7 days or as clinically indicated. The primary outcome of hyperexcitability was defined by intraoperative electrocorticography high-frequency oscillation (HFO) rates. Seizure freedom and overall survival were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and correlative biomarkers were measured by mass spectrometry., Results: HFO rates were similar between patients treated with perampanel and levetiracetam. The trial was terminated early after a planned interim analysis, and outcomes assessed in 11 patients (seven perampanel treated; four treated with SOC). Over a median 281 days of postenrollment follow-up, 27% of patients had seizures, including 14% maintained on perampanel and 50% treated with SOC. Overall survival in perampanel-treated patients was similar to that in a glioblastoma reference cohort. Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations., Conclusions: Glioma peritumoral glutamate concentrations correlated with high-gamma oscillation rates. Targeting glutamatergic activity with perampanel achieved similar electrocorticographic hyperexcitability levels as in levetiracetam-treated patients., (©2024 American Association for Cancer Research.)

Atrial fibrillation (AF) is a common arrhythmia encountered in acute and critical illness and is associated with poor short and long-term outcomes. Given the consequences of developing AF, research into prevention, prediction and treatment of this arrhythmia in the critically ill are of great potential benefit, however, study of AF in critically ill patients faces unique challenges, leading to a sparse evidence base to guide management in this population. Major obstacles to the study of AF in acute and critical illness include absence of a common definition, challenges in designing studies that capture complex etiology and assess causality, lack of a clear outcome set, difficulites in recruitment in acute environments with respect to timing, consent, and workflow, and failure to embed studies into clinical care platforms and capitalize on emerging technologies. Collaborative effort by researchers, clinicians, and stakeholders should be undertaken to address these challenges, both through interdisciplinary cooperation for the optimization of research efficiency and advocacy to advance the understanding of this common and complex arrhythmia, resulting in improved patient care and outcomes. The Symposium on Atrial Fibrillation in Acute and Critical Care was convened to address some of these challenges and propose potential solutions., (© 2024. The Author(s).)

How are societal stereotypes transmitted to individual-level group preferences? We propose that exposure to a stereotype, regardless of whether one agrees with it, can shape how one experiences and learns from interactions with members of the stereotyped group, such that it induces individual-level prejudice-a process involving the interplay of semantic knowledge and instrumental learning. In a series of experiments, participants interacted with players from two groups, described with either positive or negative stereotypes, in a reinforcement learning (RL) task presented as a money-sharing game. Although players' actual sharing rates were equated between groups, participants formed more positive reward associations with players from positively stereotyped than negatively stereotyped groups. This effect persisted even when stereotypes were described as unreliable and participants were instructed to ignore them. Computational modeling revealed that this preference was due to stereotype effects on priors regarding group members' behavior as well as the learning rates through which reward associations were updated in response to player feedback. We then show that these stereotype-induced preferences, once formed, spread unwittingly to others who observe these interactions, illustrating a pathway through which stereotypes may be transmitted and propagated between society and individuals. By identifying a mechanism through which stereotype knowledge can bypass explicit beliefs to induce prejudice, via the interplay of semantic and instrumental learning processes, these findings illuminate the impact of stereotype messages on the formation and propagation of individual-level prejudice., Competing Interests: Competing interests statement:The authors declare no competing interest.

Mutations in dynamin 2 (DNM2) have been associated with two distinct movement disorders: Charcot-Marie-Tooth neuropathies (CMT) and centronuclear myopathy (CNM). Most of these mutations are clustered in the pleckstrin homology domain (PHD), which engages in intramolecular interactions that limit dynamin self-assembly and GTPase activation. CNM mutations interfere with these intramolecular interactions and suppress the formation of the autoinhibited state. CMT mutations are located primarily on the opposite surface of the PHD, which is specialized for phosphoinositide binding. It has been speculated that the distinct locations and interactions of residues mutated in CMT and CNM explain why each set of mutations causes either one disease or the other, despite their close proximity within the PHD sequence. We previously reported that at least one CMT-causing mutant, lacking residues 555 DEE 557 (ΔDEE), displays the same inability to undergo autoinhibition as observed in CNM-linked mutants. Here, we show that both the DNM2 ΔDEE and CNM-linked DNM2 A618T mutants form larger and more stable structures on the plasma membrane than that of wild-type DNM2 (DNM2 WT ). However, DNM2 A618T forms cytoplasmic inclusions at concentrations lower than those of either DNM2 WT or DNM2 ΔDEE , suggesting that CNM-linked mutations confer more severe gain-of-function properties than the ΔDEE mutation.

Objective: To validate and update the OHTS-EGPS model predicting risk of conversion from OHT to glaucoma using electronic medical records (EMR)., Design: Evaluation and update of a risk prediction algorithm using EMRs and linked visual field (VF) tests., Participants: Newly diagnosed OHT patients attending hospital glaucoma services in England., Inclusion Criteria: IOP 22-32 mmHg (either eye); normal baseline VF test, defined as Glaucoma Hemifield Test (GHT) 'within normal range' in a reliable VF test; at least two VF tests in total; no significant ocular co-morbidities., Methods: Risk factors: age, ethnicity, sex, IOP, vertical cup-to-disc ratio, central corneal thickness, VF pattern standard deviation, family history of glaucoma, systemic hypertension, diabetes mellitus, glaucoma treatment. Glaucoma conversion was defined as two consecutive and reliable VF tests with GHT 'outside normal limits' and/or need for glaucoma surgery. For validation, the OHTS-EGPS model was applied to predict a patient's risk of developing glaucoma in 5 years. In the updating stage, the OHTS-model was re-fitted by re-estimating the baseline hazard and regression coefficients. The updated model was cross-validated and several variants were explored., Main Outcome Measures: Measures of discriminative ability (c-index) and calibration (calibration slope) were calculated and pooled across hospitals using random effects meta-analysis., Results: From a total of 138,461 patients from ten hospital glaucoma services in England 9030 patients with OHT fitted the inclusion criteria. A total of 1530 (16.9%) patients converted to glaucoma during this follow-up period. The OHTS-EGPS model provided a pooled c-index of 0.61 (95% confidence interval: 0.60, 0.63), ranging from 0.55 to 0.67 between hospitals. The pooled calibration slope was 0.45 (0.38, 0.51), ranging from 0.25 to 0.64 among hospitals. The overall re-fitted model performed better than the OHTS-EGPS model, with a pooled c-index of 0.67 (0.65, 0.69), ranging from 0.65 to 0.75 between hospitals., Conclusions: We performed an external validation of the OHTS-EGPS model in a large English population. Re-fitting the model achieved modest improvements in performance. Given the poor performance of the OHTS-EGPS model in our population, one should use caution in its application to populations that differ from those in the OHTS and EGPS., (Copyright © 2024. Published by Elsevier Inc.)

Treatment of diseases of oxidative stress through activation of the antioxidant nuclear factor E2-related factor 2 (NRF2) is limited by systemic side effects. We chemically functionalize the NRF2 activator monomethyl fumarate to require Baeyer-Villiger oxidation for release of the active drug at sites of oxidative stress. This prodrug reverses chronic pain in mice with reduced side effects and could be applied to other disorders of oxidative stress., (© 2024. The Author(s).)

PeT-based fluorescent probes were demonstrated to be powerful tools for detection and imaging, owing to their significant fluorescence enhancement in response to specific targets. While numerous examples of fluorescence-based PeT have been frequently reported, there is not even a single example of a PeT probe that operates via a chemiluminescence mode. Here we report the first PeT-based turn-on probe that acts via a chemiluminescent operation mode. We designed, synthesized, and evaluated a novel chemiluminescent probe, featuring a PeT-based turn-on mechanism. The probe consists of a phenoxy-1,2-dioxetane, linked to an azide unit that acts as a PeT quencher. Upon cycloaddition of a strained cycloalkyne with the azide, a triazole-dioxetane is formed, which undergoes relatively slow chemiexcitation, resulting in a measurement window with an exceptionally high signal-to-noise ratio (over 5000-fold). The PeT-dioxetane probe could effectively detect and image two model proteins labeled with strained cycloalkyne units (Myc-DBCO and Max-DBCO) through either NHS or maleimide conjugations. Comparative analysis shows that our PeT-based chemiluminescent probe significantly outperforms a commercially available fluorescent analog. We anticipate that the insights gained from this study will facilitate the development of additional chemiluminescent probes utilizing various PeT-quenching pathways., (© 2024 Wiley‐VCH GmbH.)

In epidemiological studies, the measurements of disease outcomes are carried out by different evaluators. In this paper, we propose a two-stage procedure for detecting outlier evaluators. In the first stage, a regression model is fitted to obtain the evaluators' effects. Outlier evaluators have different effects than normal evaluators. In the second stage, stepwise hypothesis tests are performed to detect outlier evaluators. The true positive rate and true negative rate of the proposed procedure are assessed in a simulation study. We apply the proposed method to detect potential outlier audiologists among the audiologists who measured hearing threshold levels of the participants in the Audiology Assessment Arm of the Conservation of Hearing Study, which is an epidemiological study for examining risk factors of hearing loss., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Pterosaurs, the first true flying vertebrates, played a crucial role in Mesozoic terrestrial ecosystems. However, our understanding of their ability to move around on the ground and, more broadly, their terrestrial paleoecology remains limited. Here, we demonstrate an unexpectedly high degree of variation in the hands and feet of pterosaurs, comparable with that observed in extant birds. This suggests that pterosaurs were adapted to a remarkably broad range of non-aerial locomotor ecologies. Small, early, long-tailed pterosaurs (non-pterodactyliforms) exhibit extreme modifications in their hand and foot proportions indicative of climbing lifestyles. By contrast, the hands and feet of later, short-tailed pterosaurs (pterodactyliforms) typically exhibit morphologies consistent with more ground-based locomotor ecologies. These changes in proportions correlate with other modifications to pterosaur anatomy, critically, the separation along the midline of the flight membrane (cruropatagium) that linked the hindlimbs, enabling a much more effective locomotory ability on the ground. Together, these changes map a significant event in tetrapod evolution: a mid-Mesozoic colonization of terrestrial environments by short-tailed pterosaurs. This transition to predominantly ground-based locomotor ecologies did not occur as a single event coinciding with the origin of short-tailed forms but evolved independently within each of the four principal radiations: euctenochasmatians, ornithocheiroids, dsungaripteroids, and azhdarchoids. Invasion of terrestrial environments by pterosaurs facilitated the evolution of a wide range of novel feeding ecologies, while the freedom from limitations imposed by climbing permitted an increase in body size, ultimately enabling the evolution of gigantism in multiple lineages., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Darunavir is a potent HIV protease inhibitor with a high barrier to resistance. We conducted a nested pharmacokinetic sub-study within CHAPAS-4 to evaluate darunavir exposure in African children with HIV, taking once-daily darunavir/ritonavir for second-line treatment., Methods: We used data from the CHAPAS-4 pharmacokinetic sub-study treating children with once-daily darunavir/ritonavir (600/100 mg if 14-24.9 kg and 800/100 mg if ≥25 kg) with either tenofovir alafenamide fumarate (TAF)/emtricitabine (FTC), abacavir/lamivudine or zidovudine/lamivudine. Steady-state pharmacokinetic sampling was done at 0, 1, 2, 4, 6, 8, 12 and 24 hours after observed darunavir/ritonavir intake. Non-compartmental and population pharmacokinetic analyses were used to describe the data and identify significant covariates. Reference adult pharmacokinetic data were used for comparison. We simulated the World Health Organization (WHO) recommended 600/100 mg darunavir/ritonavir dose for the 25-34.9 kg weight band., Results: Data from 59 children with median age and weight 10.9 (range 3.8-14.7) years and 26.0 (14.5-47.0) kg, respectively, were available. A two-compartment disposition model with transit absorption compartments and weight-based allometric scaling of clearance and volume best described darunavir data. Our population achieved geometric mean (%CV) darunavir AUC0-24h, 94.3(50) mg·h/L and Cmax, 9.1(35) mg/L, above adult reference values and Ctrough, 1.5(111) mg/L, like adult values. The nucleoside reverse-transcriptase inhibitor backbone was not found to affect darunavir concentrations. Simulated WHO-recommended darunavir/ritonavir doses showed exposures equivalent to adults. Higher alpha-1-acid glycoprotein increased binding to darunavir and decreased apparent clearance of darunavir., Conclusions: Darunavir exposures achieved in our trial are within safe range. Darunavir/ritonavir can safely be co-administered with TAF/FTC. Both WHO-recommended 600/100 mg and CHAPAS-4 800/100 mg darunavir/ritonavir doses for the 25-34.9 kg weight band offer favourable exposures. The choice between them can depend on tablet availability., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

A DFT analysis of the Fenton and Fenton-like reactions points out that the pH effect on the nature of the oxidizing intermediate formed is due to a pK a of the peroxide when hydroperoxides are used. When S 2 O 8 2- is used, the pH effect is due to the pK a of one of the water ligands of the central iron cation. The results suggest that the choice of the hydroperoxide and the ligands present affects the pH at which the transition from the formation of hydroxyl radicals to the formation of Fe IV =O aq occurs., (© 2024 Wiley-VCH GmbH.)

Immunoglobulin E (IgE)-mediated food allergies are the most common type of food allergy, often causing rapid symptoms after exposure to allergens posing a serious health risk and a high impact on patient's and caregiver's quality of life. Omalizumab, a humanized anti-IgE monoclonal antibody, reduces allergic reactions by binding to circulating IgE. Omalizumab has been successfully used in allergic asthma, chronic rhinosinusitis with nasal polyps, and chronic urticaria, and was recently approved for treating IgE-mediated food allergies by the US Food and Drug Administration (FDA). This GA 2 LEN ANACARE Consensus Statement presents our position on the use of omalizumab for treating IgE-mediated food allergies, based on a systematic review and meta-analysis, experience with use for other conditions, and expert consensus achieved via an eDelphi process. Following publication of the recent OUtMATCH study (stage 1) results and subsequent FDA approval, we propose that there is now sufficient evidence to recommend omalizumab as the only drug currently available that can mechanistically reduce IgE-mediated food allergic reactions. We acknowledge that the evidence does not reach the highest level of evidence which would be needed for a guideline recommendation., (© 2024 The Author(s). Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Interleukin-2 (IL-2) variants with increased CD25 dependence that selectively expand Foxp3 + regulatory T (T R ) cells are in clinical trials for treating inflammatory diseases. Using an Fc-fused IL-2 mutein (Fc.IL-2 mutein) we developed that prevents diabetes in non-obese diabetic (NOD) mice, we show that Fc.IL-2 mutein induced an activated T R population with elevated proliferation, a transcriptional program associated with Stat5- and T cell receptor-dependent gene modules, and high IL-10 and CTLA-4 expression. Increased IL-10 signaling limited surface major histocompatibility complex class II upregulation during conventional dendritic cell (cDC) maturation, while increased CTLA-4-dependent transendocytosis led to the transfer of CD80 and CD86 co-stimulatory ligands from maturing cDCs to T R cells. In NOD mice, Fc.IL-2 mutein treatment promoted the suppression of cDCs in the inflamed pancreas and pancreatic lymph nodes, resulting in T cell anergy. Thus, IL-2 mutein-expanded T R cells have enhanced functional properties and restrict cDC function, offering promise for targeted immunotherapy use in autoimmune disease., Competing Interests: Declaration of interests D.J.C. is a member of the scientific advisory board and holds stock options in Sonoma Biotherapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Clinicians managing patients with acute recreational drug or new psychoactive substance toxicity typically depend on self-reported drug(s) used. This study compares patient self-report (and/or from other sources) to the substance(s) that were subsequently identified in serum., Methods: A prospective sample of 1,000 adults presenting to a tertiary care, urban emergency department in London, United Kingdom, with acute recreational drug/new psychoactive substance toxicity was collected from 1 February 2019 to 2 February 2020. A total of 939 appropriate samples underwent qualitative analysis by high-resolution mass spectrometry with comparison to a database of drugs/metabolites. Data on the stated drug(s) used were extracted from the routine medical chart/records; results were batched by drug class, when appropriate, and analysis was performed using R software., Results: Seven hundred and ninety-nine (85.1%) patients were male with a median (IQR) age of 34 years (27 to 42 years). Six hundred and thirty-five (67.6%) patients reported using two or more drugs. The median (IQR) positive predictive value of a self-report substance having been taken was 0.68 (IQR: 0.44-0.86); conversely, the median negative predictive value of a substance having not been taken was 0.90 (IQR: 0.53-0.95). There was variability in the accuracy of reporting. For example, self-reported opioid use had a 90.5% likelihood that opioids were detected on analysis, whereas hallucinogens were only detected in 18.8% of samples when use was reported. Individuals were also mostly accurate in not underreporting substances. For example, those not explicitly reporting gamma-hydroxybutyrate use were 97.5% truly negative., Discussion: Overall, most users were relatively accurate in their self-report of what class of drugs they had used, although there was variability in this accuracy. However, other drugs were present even when not reported, for example, opioids with disproportionate detection of prescription and over-the-counter (non-prescription) opioids that were unreported., Conclusions: Self-report (and/or collateral reports) had overall relatively high concordance with the likelihood that a substance was, or was not, recently used. Therefore, clinicians can make initial treatment decisions based on the self-reported drug(s) used in most cases.

Competing Interests: R.P. Voermans received research funding for investigator-initiated studies from Boston Scientific and Prion Medical; he is a consultant for and receives speaker's fees from Boston Scientific. P.J.F. de Jonge received research support from FujiFilm; he has received speakers fee for Boston Scientific and Cook Medical. D.M. de Jong declares that he has no conflicts of interest.

RNA molecules form complex networks of molecular interactions that are central to their function and to cellular architecture. But these interaction networks are difficult to probe in situ. Here, we introduce Oligonucleotide-mediated proximity-interactome MAPping (O-MAP), a method for elucidating the biomolecules near an RNA of interest, within its native context. O-MAP uses RNA-fluorescence in situ hybridization-like oligonucleotide probes to deliver proximity-biotinylating enzymes to a target RNA in situ, enabling nearby molecules to be enriched by streptavidin pulldown. This induces exceptionally precise biotinylation that can be easily optimized and ported to new targets or sample types. Using the noncoding RNAs 47S, 7SK and Xist as models, we develop O-MAP workflows for discovering RNA-proximal proteins, transcripts and genomic loci, yielding a multiomic characterization of these RNAs' subcellular compartments and new regulatory interactions. O-MAP requires no genetic manipulation, uses exclusively off-the-shelf parts and requires orders of magnitude fewer cells than established methods, making it accessible to most laboratories., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Previous light-mediated approaches to the direct decarboxylative Giese aroylation reaction have mainly relied on the use of a photocatalyst and a reductive quenching pathway. By exploiting a mechanistically distinct oxidative protocol, we have successfully developed a photocatalyst-free, light-mediated direct Giese aroylation methodology.

Background: Leukocytes are induced to migrate into the uterus at parturition, releasing cytokines and chemokines that activate it for delivery. A specific chemotactic signal is required for these actions, and published evidence suggests that it comes from the human fetal membranes and has a time-dependent component (ie, cells obtained at term in labor migrate more than cells obtained at term not yet in labor). The hypothesis that the fetal membrane chemoattractants activate the leukocytes to become responsive for migration was tested., Objective: This study aimed to: (1) examine the changes in leukocyte migration-responsiveness longitudinally from the late third trimester, to in labor, to 3 days postpartum; (2) explore the specific week-to-week changes in migration before delivery; (3) define the timing of chemokine receptor expression patterns in leukocytes relative to migration and the changes in cytokine and chemokine concentrations in maternal serum; (4) examine the ability of term fetal membrane-conditioned medium and term maternal serum to increase cell responsiveness; and (5) test the potential of the leukocyte migration assay to predict delivery within 1 week., Study Design: Leukocyte migration in response to a chemoattractive extract of term human fetal membranes was studied using a modified Boyden chamber. Flow cytometry assessed migrated cell phenotypes. The relationship between the expression of chemokine receptors and migration was tested using quantitative polymerase chain reaction, the bioassay, and regression analyses. Cytokines and chemokines in maternal serum were quantified using multiplex analysis. Conditioned medium from fetal membrane explants and maternal serum were evaluated for their abilities to enhance leukocyte migration using the bioassay. The ability of the bioassay to predict term delivery was assessed using receiver-operating characteristic curve and cost-curve analysis., Results: The number of leukocytes that migrated at term delivery was increased relative to the late third trimester, followed by a significant fall in numbers that migrated at 3 days postpartum (P=.002). The largest increase in migrated cells occurred 1 to 2 weeks before delivery. The messenger RNA abundance of several chemokine receptors increased in peripheral leukocytes at term in labor relative to the third trimester, and this correlated with an increase in migrated cells in 5 of 6 cases (R=0.589 to 0.897; P<.03). The concentrations of several chemokines and cytokines in maternal serum increased with labor onset. Fetal membrane explant-conditioned medium and maternal serum obtained at term labor increased the responsiveness of leukocytes to fetal membrane chemoattractive extract. The bioassay was demonstrated to predict delivery within 7 days with excellent performance characteristics using a cohort prevalence of 71.7% (positive predictive value=96.1%; negative predictive value=58.5%; sensitivity=74.2%; specificity=92.3%; positive likelihood ratio=9.25; and negative likelihood ratio=0.28). A single determination was validated to have a high degree of confidence., Conclusion: Term human fetal membranes release chemoattractants near the end of pregnancy that increase in ability to activate and attract an increasing number of leukocytes as gestation advances., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Learning Health Networks (LHN) have evolved within medicine over the past two decades, but their integration into transplantation has been more recent., Objectives and Methods: In this paper, we describe three LHNs in end-stage organ disease/transplantation, their common and unique features, and how their "actor-oriented" architecture allowed for rapid adaptation to meet the needs of their patients and practitioners during the recent COVID-19 pandemic., Result: The structure and focus of the Improving Renal Outcomes Collaborative (IROC), Starzl Network for Excellence in Pediatric Transplantation (SNEPT), and the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) are reviewed. We discuss the critical role of patient and family engagement, focusing on collaboration with Transplant Families. Finally, we review challenges common to the LHN concept and potential common areas of alignment to achieve the goal of more rapid and sustained progress to improve health in pediatric transplantation., Conclusion: LHN in transplantation are essential to accelerate knowledge dissemination and improve outcomes., (© 2024 Wiley Periodicals LLC.)

Introduction and Importance: Tubercular Immune Reconstitution Inflammatory syndrome (TB-IRIS) is defined as the worsening of existing disease or new tuberculosis lesions during anti-tuberculosis therapy after excluding drug resistance, adherence issues, secondary infection, and malignancy. Ventriculitis is a rare and detrimental complication of cerebral tuberculosis. Here, we report a case of ventriculitis as a manifestation of TB-IRIS., Case Presentation: A 46-year-old male presented to the emergency department with a decline in consciousness for four days prior to admission. He experienced a progressive headache accompanied by intermittent high-grade fever over the past week. He was diagnosed with rifampicin-sensitive pulmonary tuberculosis three months prior and was treated with a fixed-dose combination of anti-tuberculosis (ATT) regimen. His HIV test result was negative. A non-contrast computed tomography (CT) scan revealed ventriculitis and hydrocephalus. The patient subsequently received ATT and corticosteroids, along with external ventricular drainage (EVD) to alleviate intracranial pressure and address the intraventricular infection. Regrettably, the patient's condition progressively declined, resulting in his demise on the seventh day post-admission., Clinical Discussion: TB-IRIS is primarily characterized in individuals with HIV/tuberculosis coinfection; however, it does not exclude that TB-IRIS may occur in immunocompetent conditions. Tuberculous ventriculitis is a manifestation of CNS TB-IRIS, characterized by significant morbidity and mortality. The fundamental principle in managing ventriculitis is to control both the inflammation and the infection and reducing intracranial pressure., Conclusion: This particular case does not significantly enhance the management of CNS-TB-IRIS; however, it does bring attention to the potential occurrence of this condition in immunocompetent patients., Competing Interests: Declaration of competing interest We declare no conflict of interest that could inappropriately influence this work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)