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The BAF chromatin remodeler regulates lineage commitment including cranial neural crest cell (CNCC) specification. Variants in BAF subunits cause Coffin-Siris syndrome (CSS), a congenital disorder characterized by coarse craniofacial features and intellectual disability. Approximately 50% of individuals with CSS harbor variants in one of the mutually exclusive BAF subunits, ARID1A/ARID1B. While Arid1a deletion in mouse neural crest causes severe craniofacial phenotypes, little is known about the role of ARID1A in CNCC specification. Using CSS-patient-derived ARID1A +/- induced pluripotent stem cells to model CNCC specification, we discovered that ARID1A-haploinsufficiency impairs epithelial-to-mesenchymal transition (EMT), a process necessary for CNCC delamination and migration from the neural tube. Furthermore, wild-type ARID1A-BAF regulates enhancers associated with EMT genes. ARID1A-BAF binding at these enhancers is impaired in heterozygotes while binding at promoters is unaffected. At the sequence level, these EMT enhancers contain binding motifs for ZIC2, and ZIC2 binding at these sites is ARID1A-dependent. When excluded from EMT enhancers, ZIC2 relocates to neuronal enhancers, triggering aberrant neuronal gene activation. In mice, deletion of Zic2 impairs NCC delamination, while ZIC2 overexpression in chick embryos at post-migratory neural crest stages elicits ectopic delamination from the neural tube. These findings reveal an essential ARID1A-ZIC2 axis essential for EMT and CNCC delamination., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The International Mouse Phenotyping Consortium (IMPC) systematically produces and phenotypes mouse lines with presumptive null mutations to provide insight into gene function. The IMPC now uses the programmable RNA-guided nuclease Cas9 for its increased capacity and flexibility to efficiently generate null alleles in the C57BL/6N strain. In addition to being a valuable novel and accessible research resource, the production of 3313 knockout mouse lines using comparable protocols provides a rich dataset to analyze experimental and biological variables affecting in vivo gene engineering with Cas9. Mouse line production has two critical steps - generation of founders with the desired allele and germline transmission (GLT) of that allele from founders to offspring. A systematic evaluation of the variables impacting success rates identified gene essentiality as the primary factor influencing successful production of null alleles. Collectively, our findings provide best practice recommendations for using Cas9 to generate alleles in mouse essential genes, many of which are orthologs of genes linked to human disease., (© 2024. The Author(s).)

The goal of systems biology is to gain a network level understanding of how gene interactions influence biological states, and ultimately inform upon human disease. Given the scale and scope of systems biology studies, resource constraints often limit researchers when validating genome-wide phenomena and potentially lead to an incomplete understanding of the underlying mechanisms. Further, prioritization strategies are often biased towards known entities (e.g. previously studied genes/proteins with commercially available reagents), and other technical issues that limit experimental breadth. Here, heterogeneous biological information is modeled as an association graph to which a high-performance minimum dominating set solver is applied to maximize coverage across the graph, and thus increase the breadth of experimentation. First, we tested our model on retrieval of existing gene functional annotations and demonstrated that minimum dominating set returns more diverse terms when compared to other computational methods. Next, we utilized our heterogenous network and minimum dominating set solver to assist in the process of identifying understudied genes to be interrogated by the International Mouse Phenotyping Consortium. Using an unbiased algorithmic strategy, poorly studied genes are prioritized from the remaining thousands of genes yet to be characterized. This method is tunable and extensible with the potential to incorporate additional user-defined prioritizing information. The minimum dominating set approach can be applied to any biological network in order to identify a tractable subset of features to test experimentally or to assist in prioritizing candidate genes associated with human disease., (© 2024. The Author(s).)

Fully relativistic calculations, primarily at the 4-component coupled-cluster singles and doubles with perturbative triples [CCSD(T)] level of theory with the Dirac-Coulomb (DC) Hamiltonian, have been carried out for the superheavy (E125)F molecule using large Gaussian basis sets. The electronic ground state is determined to have an [Og]8s25g16f3 configuration on E125 with an Ω = 6 ground state and an 8p electron largely donated to F. A Mulliken population analysis indicates that the ground state is mainly ionic with a partial charge of +0.79 on E125 and a single sigma bond involving the F 2p and E125 8p spinors. The occupied g spinor is not involved in the bonding. With the largest basis set used in this work, the (0 K) dissociation energy was calculated at the DC-CCSD(T) level of theory to be 7.02 eV. Analogous calculations were also carried out for the E125 atom, both the neutral and its cation. The lowest energy electron configuration of E125+, [Og]8s1/225g7/216f5/23 with a J = 6 ground state, was found to be similar to that in (E125)F, while the neutral E125 atom has an [Og]8s1/225g7/216f5/227d3/218p1/21 ground state electron configuration with a J = 17/2 ground state. The ionization energy (IE) of E125 is reported for the first time and is calculated to be 4.70 eV at the DC-CCSD(T) level of theory. Non-relativistic calculations were also carried out on the E125 atom and the (E125)F molecule. The non-relativistic ground state of the E125 atom was calculated to have a 5g5 ground state with an IE of just 3.4 eV. The net effect of relativity on (E125)F is to stabilize its bonding., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

A new computational framework for spinor-based relativistic exact two-component (X2C) calculations is developed using contracted basis sets with a spin-orbit contraction scheme. Generally contracted, j-adapted basis sets of p-block elements using primitive functions in the correlation-consistent basis sets are constructed for the X2C Hamiltonian with atomic mean-field spin-orbit integrals (the X2CAMF scheme). The contraction coefficients are taken from atomic X2CAMF Hartree-Fock spinors, thereby following the simple concept of a linear combination of atomic orbitals. Benchmark calculations of spin-orbit splittings, equilibrium bond lengths, and harmonic vibrational frequencies demonstrate the accuracy and efficacy of the j-adapted spin-orbit contraction scheme., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Background: The Index of Severity for Eosinophilic Esophagitis (I-SEE) is a new expert-defined clinical tool that classifies disease severity of eosinophilic esophagitis (EoE)., Objective: We aimed to determine whether I-SEE is associated with patient characteristics, molecular features of EoE, or both., Methods: We analyzed a prospective cohort of patients with EoE from the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Associations between I-SEE and clinical and molecular features (assessed by an EoE diagnostic panel [EDP]) were assessed., Results: In 318 patients with chronic EoE (209 adults, 109 children), median total I-SEE score was 7.0, with a higher symptoms and complications score in children than adults (4.0 vs 1.0; P < .001) and higher inflammatory and fibrostenotic features scores in adults than children (3.0 vs 1.0 and 3.0 vs 0, respectively; both P < .001). Total I-SEE score had a bimodal distribution with the inactive to moderate categories and severe category. EDP score correlated with total I-SEE score (r = -0.352, P < .001) and both inflammatory and fibrostenotic features scores (r = -0.665, P < .001; r = -0.446, P < .001, respectively), but not with symptoms and complications scores (r = 0.047, P = .408). Molecular severity increased from inactive to mild and moderate, but not severe, categories. Longitudinal changes of modified I-SEE scores and inflammatory and fibrostenotic features scores reflected histologic and molecular activity., Conclusions: I-SEE score is associated with select clinical features across severity categories and with EoE molecular features for nonsevere categories, warranting further validation., Competing Interests: Disclosure statement Supported by National Institutes of Health (NIH) grant K99/R00 AI158660 (to T.S.) and the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR, U54 AI117804), which is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS), and is cofunded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NCATS, and in part by the Intramural Research Program of NIAID. CEGIR is also supported by patient advocacy groups, including the American Partnership for Eosinophilic Disorders (APFED), Campaign Urging Research for Eosinophilic Disease (CURED), and Eosinophilic Family Coalition (EFC). As a member of the RDCRN, CEGIR is also supported by its Data Management and Coordinating Center (DMCC) (U2CTR002818). Funding support for the DMCC is provided by NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). This project was supported in part by NIH P30 DK078392 (Gene Expression Core, Pathology Research Core, and Confocal Imaging Core) of the Digestive Diseases Research Core Center in Cincinnati. Disclosure of potential conflict of interest: E. S. Dellon is consultant for Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/ Bristol Meyers Squibb (BMS), Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio. E. S. Dellon has received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda; and has received educational grants from Allakos, Holoclara, and Invea. S. S. Aceves is disease state awareness speaker and consultant for Sanofi/Regeneron, consultant for Ferring Pharma; has research funding from Implicit Biosciences and BMS; and is a coinventor of oral viscous budesonide UCSD patent, Takeda license. M. Chehade served as consultant for Regeneron, Adare/Ellodi, AstraZeneca, Sanofi, BMS, Allakos, Shire/Takeda, Phathom, Recludix Pharma, Nexstone Immunology; and received research funding from Regeneron, Allakos, AstraZeneca, Adare/Ellodi, BMS, Danone, and Shire/Takeda. M. H. Collins is consultant for Allakos, Arena Pharmaceuticals, AstraZeneca, BMS, Calypso Biotech, EsoCap Biotech, GlaxoSmithKline, Receptos/Celgene, Regeneron Pharmaceuticals, Robarts Clinical Trials/Alimentiv, Sanofi, and Shire/Takeda. C. M. Davis receives research funding from the NIH/NIAID (U01AI126614, UM2AI130836, U54AI117804), DBV Technologies, Aimmune Therapeutics, Regeneron Pharmaceuticals, Takeda, and Allergenis. G. W. Falk is consultant for Ellodi, Sanofi/Regeneron, BMS/Celgene, Takeda, Ubiquity Bio, and Phathom Pharmaceuticals; and receives research funding from Arena/Pfizer, Ellodi, Sanofi/Regeneron, BMS/Celgene, Takeda, Allakos, Nexteos, and Celldex Therapeutics. G. T. Furuta receives research funding from Pfizer/Arena; is consultant for Sanofi/Regeneron and BMS; and is chief medical officer for EnteroTrack. N. P. Gonsalves is consultant for Allakos, AstraZeneca, BMS, and Sanofi/Regeneron; is speaker for Sanofi/Regeneron; and receives publication royalties from UpToDate. S. K. Gupta is consultant/data safety monitoring board member of Adare, BMS, QOL, Takeda, MedScape, PVI, ViaSkin, and UpToDate; and receives research funding from Allakos, Ellodi, and AstraZeneca. I. Hirano has received research funding from Ellodi/Adare, Allakos, Pfizer/Arena Pharmaceuticals, AstraZeneca, Meritage Pharma, Receptos/Celgene, Sanofi, Regeneron, and Shire/Takeda; and is is consultant for Ellodi/Adare, Allakos, AstraZeneca, BMS/Receptos/Celgene, Calyx/Parexel, EsoCap Biotech, Gossamer Bio, Lilly, Meritage Pharma, Pfizer/Arena Pharmaceuticals, Phathom, Sanofi/Regeneron, and Shire/Takeda. K. A. Peterson is consultant/advisory for AGA, Alladapt, AstraZeneca, Allakos, BMS, Ellodi, Invea, Lucid, Nexstone, WebMD, Peerview, Regeneron, Revolo, Takeda, and WebMD; receives research funding from AstraZeneca, Allakos, Regeneron-Sanofi, Revolo, Adare, Ellodi, BMS, and Celldex; is speaker for AGA, Regeneron, Peerview, Takeda, Allakos, and WebMD; has grant support (unrestricted) from Allakos; and has equity in Nexeos Bio. M. A. Pletneva is consultant for Allakos and Sanofi/Regeneron. J. M. Spergel is consultant for Novartis, Regeneron, and Sanofi; and receives grant support from Regeneron and Sanofi. J. B. Wechsler is speaker for Sanofi/Regeneron; and consultant for Sanofi/Regeneron, Celldex, Celgene/Receptos/BMS, Allakos, Ellodi, and AstraZeneca. M. E. Rothenberg is consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nextstone One, BMS, AstraZeneca, Ellodi Pharma, Glaxo Smith Kline, Sanofi/Regeneron, Revolo Biotherapeutics, and Guidepoint; has equity interest in the first 6 listed; receives royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate; and is an inventor of patents owned by Cincinnati Children’s Hospital Medical Center. T. Shoda is a coinventor of patents owned by Cincinnati Children’s Hospital Medical Center. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

High-level electronic structure calculations were conducted to examine the bonding and spectroscopic properties of the UO 0/± and UF 0/± diatomic molecules. The low-lying Ω states were described by using multireference SO-CASPT2 calculations. The adiabatic electronic affinity (AEA), adiabatic ionization energy (IE), and bond dissociation energy (BDE) were calculated at the Feller-Peterson-Dixon (FPD) level. The ground state of UO is predicted to be 5 I 4 , and that of UF is 4 I 9/2 . The calculated AEAs of UO and UF are 1.123 and 0.453 eV, respectively, and the corresponding IEs are 5.976 and 6.278 eV. The BDE of UO (749.5 kJ/mol) is predicted to be considerably higher than that of UF (627.2 kJ/mol), and both are higher than those predicted for UB, UC, and UN. NBO calculations show strong ionic character for the ground states of UO and UF and bond orders that range from 2 to 3 and from 1 to 2, respectively. Comparisons of the calculated properties to those of the series comprising UB, UC, and UN diatomic molecules are given.

Background: Eosinophilic esophagitis (EoE) is a chronic, inflammatory disease of the esophagus leading to symptoms of esophageal dysfunction; dysphagia is the most common symptom experienced by adults and adolescents., Objective: We sought to perform a psychometric evaluation of the Dysphagia Symptom Questionnaire (DSQ), a patient-reported outcome measure for patients with EoE., Methods: Using baseline and week 24 data from the randomized, interventional, multinational phase 3 R668-EE-1774 trial (NCT03633617), the measurement properties of the DSQ-including reliability, construct and known-groups validity, responsiveness, and interpretation of change-were evaluated., Results: The analysis population comprised 239 patients with EoE (age [mean ± SD], 28.1 ± 13.14 years; 63.6% male; 90.4% White). Intraclass correlation coefficients of 0.92 and 0.97 exceeded the acceptable reliability threshold (≥0.70). Construct validity correlations with EoE symptom and impact measures were moderate at baseline (| r | = 0.44-0.55) and week 24 (| r | = 0.55-0.69), and the DSQ biweekly total score discriminated among groups defined by disease severity. Analyses exploring interpretation of change from baseline on the DSQ biweekly total score indicated thresholds for within-patient improvement ranging from 9 to 23 points; a within-patient improvement from baseline of 13 points or greater could be considered clinically meaningful., Conclusions: This analysis confirmed that the DSQ has acceptable distributional properties, test-retest reliability, construct validity, and ability to detect change. Therefore, the DSQ is a valid and reliable measure to assess the patient-reported symptom of dysphagia among adult and adolescent patients with EoE in the context of a clinical trial setting., Competing Interests: Regeneron Pharmaceuticals, Inc, and Sanofi Global provided the financial support for the study. RTI Health Solutions, an independent nonprofit research organization, received funding under a research contract with Regeneron Pharmaceuticals, Inc, and Sanofi Global to conduct this study and provide publication support in the form of manuscript writing, styling, and submission. Disclosure of potential conflict of interest: E. S. Dellon has received research funding from Adare/Ellodi, 10.13039/100030947Allakos, Arena/Pfizer, AstraZeneca, 10.13039/100004330GlaxoSmithKline, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda; is a consultant for Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, 10.13039/501100024061Eupraxia, 10.13039/501100003122Ferring, 10.13039/100004330GlaxoSmithKline, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology, 10.13039/100031219Nutricia, 10.13039/100016751Parexel/Calyx, Phathom, 10.13039/100009857Regeneron, Revolo, Robarts/Alimentiv, Salix, 10.13039/100004339Sanofi, 10.13039/100007343Shire/Takeda, Target RWE, and Upstream Bio; and has received educational grants from Allakos, Holoclara, and Invea. K. A. Peterson is a consultant or advisor for AGA, Alladapt, AstraZeneca, Allakos, Bristol Meyers Squibb, Ellodi, Invea, Lucid, Nexstone, Peerview, Regeneron, Takeda, and WebMD; has received research fees from AstraZeneca, Allakos, Adare, Regeneron-Sanofi, Revolo, repSpeaker, AGA, Regeneron, Peerview, Takeda, and WebMD; has received unrestricted grant support from Allakos and Chobani; and has equity in Nexeos Bio. D. Whalley and S. Qin are employees of RTI Health Solutions. S. T. Tilton is an employee of Sanofi Global and may hold stocks and/or shares in the company. E. McCann, S. Kamat, and X. Sun are employees of Regeneron Pharmaceuticals, Inc, and may hold shares and/or stock options in the company., (© 2024 The Authors.)

A preliminary report from the recent phase 3 trial of benralizumab, a monoclonal antibody that binds to interleukin-5 receptor alpha (IL5Rα), in patients with EoE revealed that medication use led to tissue eosinophil eradication but did not meet the clinical endpoint of symptom resolution. Here, we characterized the clinical, endoscopic, histologic, and transcriptional changes in patients with active EoE following benralizumab treatment. We retrospectively examined patients with EoE treated with benralizumab at the University of Utah (n = 11) and reviewed reported clinical symptoms, circulating and tissue eosinophilia, and endoscopic and histologic scores. Gene expression profiles from available esophageal tissue from benralizumab-treated patients were compared to those from patients with remission EoE (n = 5), active EoE (n = 10), and controls (n = 22). Benralizumab treatment resulted in partial symptom improvement and significant reduction in tissue eosinophilia, and endoscopic and histologic disease scoring (P < 0.01). Histologic score reductions were driven by eosinophil feature scores, while scores for epithelial features (basal cell hyperplasia and dilated intercellular spaces) were similar to those in active EoE. The gene signatures in benralizumab-treated patients mimicked those of active EoE (e.g. upregulation of POSTN, CDH26, CCL26, and downregulation of DSG1). RNA profiles and pathways support histologic findings of impaired epithelial function that persists despite benralizumab treatment. In conclusion, despite eosinophil eradication, patients treated with benralizumab had persistent epithelial injury at the histologic and transcriptional level. In this cohort, benralizumab therapy failed to eradicate inflammation and epithelial dysfunction showing that interleukin-5 receptor alpha blockade monotherapy is insufficient to control EoE., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.)

Background Impaired glucose metabolism is characteristic of several types of dementia, preceding cognitive symptoms and structural brain changes. Reduced glucose uptake in specific brain regions, detected using fluorine 18 ( 18 F) fluorodeoxyglucose (FDG) PET, is a valuable diagnostic marker in Alzheimer disease (AD). However, the use of 18 F-FDG PET in clinical practice may be limited by equipment availability and high cost. Purpose To test the feasibility of using MRI-based deuterium ( 2 H) metabolic imaging (DMI) at a clinical magnetic field strength (3 T) to detect and localize changes in the concentration of glucose and its metabolites in the brains of patients with a clinical diagnosis of AD. Materials and Methods Participants were recruited for this prospective case-control pilot study between March 2021 and February 2023. DMI was performed at 3 T using a custom birdcage head coil following oral administration of deuterium-labeled glucose (0.75 g/kg). Unlocalized whole-brain MR spectroscopy (MRS) and three-dimensional MR spectroscopic imaging (MRSI) (voxel size, 3.2 cm cubic) were performed. Ratios of 2 H-glucose, 2 H-glutamate and 2 H-glutamine ( 2 H-Glx), and 2 H-lactate spectroscopic peak signals to 2 H-water peak signal were calculated for the whole-brain MR spectra and for individual MRSI voxels. Results A total of 19 participants, including 10 participants with AD (mean age, 68 years ± 5 [SD]; eight males) and nine cognitively healthy control participants (mean age, 70 years ± 6; six males) were evaluated. Whole-brain spectra demonstrated a reduced ratio of 2 H-Glx to 2 H-glucose peak signals in participants with AD compared with control participants (0.41 ± 0.09 vs 0.58 ± 0.20, respectively; P = .04), suggesting an impairment of oxidative glucose metabolism in AD. However, there was no evidence of localization of these changes to the expected regions of metabolic impairment at MRSI, presumably due to insufficient spatial resolution. Conclusion DMI at 3 T demonstrated impairment of oxidative glucose metabolism in the brains of patients with AD but no evidence of regional signal differences. © RSNA, 2024 Supplemental material is available for this article.

Background: Benralizumab is an eosinophil-depleting anti-interleukin-5 receptor α monoclonal antibody. The efficacy and safety of benralizumab in patients with eosinophilic esophagitis are unclear., Methods: In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial, we assigned patients 12 to 65 years of age with symptomatic and histologically active eosinophilic esophagitis in a 1:1 ratio to receive subcutaneous benralizumab (30 mg) or placebo every 4 weeks. The two primary efficacy end points were histologic response (≤6 eosinophils per high-power field) and the change from baseline in the score on the Dysphagia Symptom Questionnaire (DSQ; range, 0 to 84, with higher scores indicating more frequent or severe dysphagia) at week 24., Results: A total of 211 patients underwent randomization: 104 were assigned to receive benralizumab, and 107 were assigned to receive placebo. At week 24, more patients had a histologic response with benralizumab than with placebo (87.4% vs. 6.5%; difference, 80.8 percentage points; 95% confidence interval [CI], 72.9 to 88.8; P<0.001). However, the change from baseline in the DSQ score did not differ significantly between the two groups (difference in least-squares means, 3.0 points; 95% CI, -1.4 to 7.4; P = 0.18). There was no substantial between-group difference in the change from baseline in the Eosinophilic Esophagitis Endoscopic Reference Score, which reflects endoscopic abnormalities. Adverse events were reported in 64.1% of the patients in the benralizumab group and in 61.7% of those in the placebo group. No patients discontinued the trial because of adverse events., Conclusions: In this trial involving patients 12 to 65 years of age with eosinophilic esophagitis, a histologic response (≤6 eosinophils per high-power field) occurred in significantly more patients in the benralizumab group than in the placebo group. However, treatment with benralizumab did not result in fewer or less severe dysphagia symptoms than placebo. (Funded by AstraZeneca; MESSINA ClinicalTrials.gov number, NCT04543409.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: The mechanistic basis of the variable symptomatology seen in eosinophilic esophagitis (EoE) remains poorly understood., Objective: We examined the correlation of a validated, patient-reported outcome metric with a broad spectrum of esophageal transcripts to uncover potential symptom pathogenesis., Methods: We extracted data from 146 adults with EoE through the Consortium of Eosinophilic Gastrointestinal Disease Researchers. Patients were subgrouped by esophageal dilation history. We compared a validated patient-reported outcome metric, the EoE Activity Index (EEsAI), with a set of transcripts expressed in the esophagus of patients with EoE, the EoE Diagnostic Panel (EDP). We used single-cell RNA sequencing data to identify the cellular source of EEsAI-related EDP genes and further analyzed patients with mild and severe symptoms., Results: The EEsAI correlated with the EDP total score, especially in patients without recent esophageal dilation (r = -0.31; P = .003). We identified 14 EDP genes that correlated with EEsAI scores (r ≥ 0.3; P < .05). Of these, 11 were expressed in nonepithelial cells and three in epithelial cells. During histologic remission, only four of 11 nonepithelial genes (36%) versus all three epithelial genes (100%) had decreased expression to less than 50% of that in active EoE. Fibroblasts expressed five of 11 nonepithelial EEsAI-associated EDP genes (45%). A subset of nonepithelial genes (eight of 11; 73%), but not EoE-representative genes (none of four; 0%; CCL26, CAPN14, DSG1, and SPINK7), was upregulated in patients with EoE with the highest versus lowest symptom burden., Conclusion: The correlation of symptoms and nonepithelial esophageal gene expression substantiates that nonepithelial cells (eg, fibroblasts) likely contribute to symptom severity., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: The demographic characteristics of patients with eosinophilic gastrointestinal diseases (EGIDs) are poorly understood. Population-based assessments of EGID demographics may indicate health disparities in diagnosis., Objectives: We aimed to characterize the demographic distribution of EGIDs and evaluate the potential for bias in reporting patient characteristics., Methods: We conducted a systematic review, extracting data on age, sex, gender, race, ethnicity, body mass index, insurance, and urban/rural residence on EGID patients and the source population. Differences in proportions were assessed by chi-square tests. Demographic reporting was compared to recent guidelines., Results: Among 50 studies that met inclusion/exclusion criteria, 12 reported ≥1 demographic feature in both EGID and source populations. Except for age and sex or gender, demographics were rarely described (race = 4, ethnicity = 1, insurance = 1) or were not described (body mass index, urban/rural residence). A higher proportion of male subjects was observed for EoE or esophageal eosinophilia relative to the source population, but no difference in gender or sex distribution was observed for other EGIDs. "Sex" and "gender" were used interchangeably, and frequently only the male proportion was reported. Reporting of race and ethnicity was inconsistent with guidelines., Conclusion: Current data support a male predominance for EoE only. Evidence was insufficient to support enrichment of EGIDs in any particular racial, ethnic, or other demographic group. Population-based studies presenting demographics on both cases and source populations are needed. Implementation of guidelines for more inclusive reporting of demographic characteristics is crucial to prevent disparities in timely diagnosis and management of patients with EGIDs., Competing Interests: Supported by U54AI117804 (Consortium of Eosinophilic Gastrointestinal Disease Researchers), which is part of the Rare Disease Clinical Research Network, an initiative of the Office of Rare Disease Research, National Center for Advancing Translational Sciences (NCATS), and is funded through collaboration between the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Diabetes and Digestive and Kidney Diseases, NCATS, and patient advocacy groups including the American Partnership for Eosinophilic Disorders, Campaign Urging Research for Eosinophilic Disease (CURED), and Eosinophilic Family Coalition (EFC). This work was also funded in part by the Division of Intramural Research, NIAID, National Institutes of Health. Disclosure of potential conflict of interest: M. Chehade served as consultant for Regeneron, Allakos, Adare/Ellodi, Shire/Takeda, AstraZeneca, Sanofi, Bristol Myers Squibb, Phathom, Recludix Pharma, and Nexstone Immunology; and received research funding from Regeneron, Allakos, Shire/Takeda, AstraZeneca, Adare/Ellodi, Danone, and Bristol Myers Squibb. A. B. Muir has served on medical advisory board for Bristol Myers Squibb and Nexstone Immunology; and has received research funding from Morphic. M. H. Collins has received research funding from AstraZeneca, Ception, GSK, Meritage Pharma Inc, Receptos/Celgene/BMS, Regeneron Pharmaceuticals and Shire, a Takeda company; and is consultant for Allakos, Arena Pharmaceuticals, AstraZeneca, Calypso Biotech, EsoCap Biotech, GlaxoSmithKline, Receptos/Celgene/BMS, Regeneron Pharmaceuticals, Robarts Clinical Trials Inc/Alimentiv Inc and Shire, a Takeda company. C. M. Davis has received research funding from the National Institutes of Health/National Institute of Allergy and Infectious Disease (Consortium of Food Allergy Research/Consortium of Eosinophilic Gastrointestinal Researchers), DBV Technologies, DBV, Aimmune Therapeutics, Regeneron Pharmaceuticals, and Allergenis. G. T. Furuta is chief medical officer at EnteroTrack; consultant for Shire/Takeda; and has received grant funding from Arena and Holoclara. S. Gupta is consultant/data safety and monitoring board member or author for Adare, BMS, QOL, Takeda, MedScape, PVI, ViaSkin, and UpToDate; and has received research support from Allakos, Ellodi, and AstraZeneca. P. Khoury has received research funding from American Partnership for Eosinophilic Disorders. K. A. Peterson is consultant or served as advisor for AGA, Alladapt, AstraZeneca, Allakos, Bristol Meyers Squibb, Ellodi, Lucid, Nexstone, Peerview, Regeneron, Takeda, and WebMD; has received research support from AstraZeneca, Allakos, Adare, Regeneron-Sanofi, and Revolo; served as speaker for AGA, Regeneron, Peerview, Takeda, Allakos, and WebMD; received grant support (unrestricted) from Allakos and Chobani; and holds equity in Nexeos Bio. E. T. Jensen has received consultant fees from Regeneron, Jazz Pharmaceuticals, and TARGET-RWE. The rest of the authors declare that they have no relevant conflicts of interest., (© 2024 The Author(s).)

In this work, properties related to antioxidant-potential mechanisms (such as the bond dissociation enthalpy, BDE, for the homolytic cleavage of the O-H bond and ionization energies, IEs) were determined for phenol, pyrocatechol, and gallic acid (GA). Both the protonated and deprotonated forms of GA were investigated. The Feller-Peterson-Dixon (FPD) composite method was employed with a variety of computational approaches, i.e., density functional theory, Möller-Plesset perturbation theory, and coupled-cluster-based methods, in combination with large correlation consistent basis sets with extrapolation to the complete basis set limit and consideration of core electron correlation effects. FPD results were compared to experimental and computational data available in the literature, presenting good agreement. For example, the FPD BDE (298 K) obtained for phenol, which was based on valence-correlated MP2/CBS calculations with contributions from correlating all electrons, was determined to be 87.56 kcal/mol, a value that is 0.42 kcal/mol lower than the result obtained in the most recent experiments, 87.98 ± 0.62. Calibration against coupled-cluster calculations was also carried out for phenol. We expect that the outcomes gathered here may help in establishing a general protocol for computational chemists that are interested in determining antioxidant-related properties for phenolic compounds with considerable accuracy as well as to motivate future IE measurements (particularly for GA) to be accomplished in the near future.

Obtaining the complex refractive index vectors n ( ν ~) and k ( ν ~) allows calculation of the (infrared) reflectance spectrum that is obtained from a solid in any of its many morphological forms. We report an adaptation to the KBr pellet technique using two gravimetric dilutions to derive quantitative n ( ν ~)/ k ( ν ~) for dozens of powders with greater repeatability. The optical constants of bisphenol A and sucrose are compared to those derived by other methods, particularly for powdered materials. The variability of the k values for bisphenol A was examined by 10 individual measurements, showing an average coefficient of variation for k peak heights of 5.6%. Though no established standards exist, the pellet-derived k peak values of bisphenol A differ by 11% and 31% from their single-angle- and ellipsometry-derived values, respectively. These values provide an initial estimate of the precision and accuracy of complex refractive indices that can be derived using this method. Limitations and advantages of the method are discussed, the salient advantage being a more rapid method to derive n / k for those species that do not readily form crystals or specular pellets.

Background & Aims: Achalasia has been assumed to be an autoimmune disease targeting esophageal myenteric neurons. Recently, we proposed an alternative hypothesis that achalasia sometimes might be allergy-driven, caused by a form of eosinophilic esophagitis (EoE) in which activated eosinophils and/or mast cells infiltrating esophageal muscle release products that disrupt motility and damage myenteric neurons. To seek epidemiologic support for this hypothesis, we identified patients with achalasia in the Utah Population Database, and explored their frequency of having EoE and other allergic disorders., Methods: We used International Classification of Diseases codes to identify patients with achalasia and allergic disorders including EoE, asthma, atopic dermatitis, contact dermatitis, allergic rhinitis, allergic conjunctivitis, hives/urticaria, and anaphylaxis. We calculated relative risk (RR) for each allergic disorder by comparing the number observed in patients with achalasia with the expected number in individuals matched for birthyear and sex, and we performed subanalyses for patients age ≤40 versus age >40 years., Results: Among 844 patients with achalasia identified (55% female; median age at diagnosis, 58 years), 402 (47.6%) had ≥1 allergic disorder. Fifty-five patients with achalasia (6.5%) had EoE (1.67 EoE cases expected), for a RR of 32.9 (95% confidence interval, 24.8-42.8; P < .001). In 208 patients with achalasia age ≤40 years, the RR for EoE was 69.6 (95% confidence interval, 46.6-100.0; P < .001). RR also was increased significantly for all other allergic disorders evaluated (all greater than 3-fold higher than population rates)., Conclusions: Achalasia is strongly associated with EoE and other allergic disorders. These data support the hypothesis that achalasia sometimes might have an allergic etiology., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Clinical variants of primary progressive aphasia (PPA) are diagnosed based on characteristic patterns of language deficits, supported by corresponding neural changes on brain imaging. However, there is (i) considerable phenotypic variability within and between each diagnostic category with partially overlapping profiles of language performance between variants and (ii) accompanying non-linguistic cognitive impairments that may be independent of aphasia magnitude and disease severity. The neurobiological basis of this cognitive-linguistic heterogeneity remains unclear. Understanding the relationship between these variables would improve PPA clinical/research characterisation and strengthen clinical trial and symptomatic treatment design. We address these knowledge gaps using a data-driven transdiagnostic approach to chart cognitive-linguistic differences and their associations with grey/white matter degeneration across multiple PPA variants., Methods: Forty-seven patients (13 semantic, 15 non-fluent, and 19 logopenic variant PPA) underwent assessment of general cognition, errors on language performance, and structural and diffusion magnetic resonance imaging to index whole-brain grey and white matter changes. Behavioural data were entered into varimax-rotated principal component analyses to derive orthogonal dimensions explaining the majority of cognitive variance. To uncover neural correlates of cognitive heterogeneity, derived components were used as covariates in neuroimaging analyses of grey matter (voxel-based morphometry) and white matter (network-based statistics of structural connectomes)., Results: Four behavioural components emerged: general cognition, semantic memory, working memory, and motor speech/phonology. Performance patterns on the latter three principal components were in keeping with each variant's characteristic profile, but with a spectrum rather than categorical distribution across the cohort. General cognitive changes were most marked in logopenic variant PPA. Regardless of clinical diagnosis, general cognitive impairment was associated with inferior/posterior parietal grey/white matter involvement, semantic memory deficits with bilateral anterior temporal grey/white matter changes, working memory impairment with temporoparietal and frontostriatal grey/white matter involvement, and motor speech/phonology deficits with inferior/middle frontal grey matter alterations., Conclusions: Cognitive-linguistic heterogeneity in PPA closely relates to individual-level variations on multiple behavioural dimensions and grey/white matter degeneration of regions within and beyond the language network. We further show that employment of transdiagnostic approaches may help to understand clinical symptom boundaries and reveal clinical and neural profiles that are shared across categorically defined variants of PPA., (© 2023. The Author(s).)

Background: When children are injured or have surgery, parents can be hesitant to fill opioid prescriptions and youth may be concerned about using these medications to manage pain. Parents cite a myriad of reasons why they worry about their child using opioids. The MedSMA℞T Families intervention, which includes a Family Medication Safety Plan (FMSP), is a tool designed to support families in learning and communicating about safe prescription opioid use in their homes and with health care providers., Objective: This study's first aim was to examine adolescents' experiences with using the FMSP. The second aim of this study was to identify opportunities for future improvement., Methods: Adolescents, aged 12-18 years, were recruited from April 2021 to October 2021. They were recruited through Qualtrics research panels, email listservs, social media, and snowball sampling. Adolescents reviewed the FMSP and then completed a semistructured follow-up interview with a study team member virtually. The interviews were professionally transcribed verbatim, reviewed by the study team for accuracy, and downloaded into NVivo for analysis. Main themes were identified using content and thematic analysis., Results: Adolescents (N = 65) reviewed the FMSP and participated in the study. Adolescents found the FMSP to be acceptable and useful for prompting discussions with parents about not only opioids, but all medications being used by the youth. Study participants suggested key improvements such as the creation of a kid-friendly or Spanish language version to improve accessibility and uptake by a diverse population of teens., Conclusion: Adolescents reported that the FMSP would be a helpful tool for their families. Implementing this tool at the point of prescribing or dispensing is a potential strategy to reduce the rates of opioid misuse, reduce hesitancy, and allow adolescents more agency regarding their health care and medication management., Competing Interests: Disclosure The authors declare no relevant conflicts of interest or financial relationships., (Copyright © 2023 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Objective: Identify the improvement in diabetes performance measures and population-based clinical outcomes resulting from changes in care management processes (CMP) in primary care practices over 3 years., Research Design and Methods: This repeated cross-sectional study tracked clinical performance measures for all diabetes patients seen in a cohort of 330 primary care practices in 2017 and 2019. Unit of analysis was patient-year with practice-level CMP exposures. Causal inference is based on dynamic changes in individual CMPs between years by practice. We used the Bayesian method to simultaneously estimate a five-outcome model: A1c, systolic and diastolic blood pressure, guideline-based statin use, and Optimal Diabetes Care (ODC). We control for unobserved time-invariant practice characteristics and secular change. We modeled correlation of errors across outcomes. Statistical significance was identified using 99% Bayesian credible intervals (analogous to P < 0.01)., Results: Implementation of 18 of 62 CMPs was associated with statistically significant improvements in patient outcomes. Together, these resulted in 12.1% more patients meeting ODC performance measures. Different CMPs affected different outcomes. Three CMPs accounted for 47% of the total ODC improvement, 68% of A1c decrease, 21% of SBP reduction, and 55% of statin use increase: 1) systems for identifying and reminding patients due for testing, 2) after-visit follow-up by a nonclinician, and 3) guideline-based clinician reminders for preventive services during a clinic visit., Conclusions: Effective quality improvement in primary care focuses on practice redesign that clearly improves diabetes outcomes. Tailoring CMP adoption in primary care provides effective improvement in ODC performance through focused changes in diabetes outcomes., (© 2023 by the American Diabetes Association.)

Objective: We aimed to determine whether mepolizumab, an anti-IL-5 antibody, was more effective than placebo for improving dysphagia symptoms and decreasing oesophageal eosinophil counts in eosinophilic oesophagitis (EoE)., Methods: We conducted a multicentre, randomised, double-blind, placebo-controlled, trial. In the first part, patients aged 16-75 with EoE and dysphagia symptoms (per EoE Symptom Activity Index (EEsAI)) were randomised 1:1 to 3 months of mepolizumab 300 mg monthly or placebo. Primary outcome was change in EEsAI from baseline to month 3 (M3). Secondary outcomes included histological, endoscopic and safety metrics. In part 2, patients initially randomised to mepolizumab continued 300 mg monthly for 3 additional months (mepo/mepo), placebo patients started mepolizumab 100 mg monthly (pbo/mepo), and outcomes were reassessed at month 6 (M6)., Results: Of 66 patients randomised, 64 completed M3, and 56 completed M6. At M3, EEsAI decreased 15.4±18.1 with mepolizumab and 8.3±18.0 with placebo (p=0.14). Peak eosinophil counts decreased more with mepolizumab (113±77 to 36±43) than placebo (146±94 to 160±133) (p<0.001). With mepolizumab, 42% and 34% achieved histological responses of <15 and ≤6 eos/hpf compared with 3% and 3% with placebo (p<0.001 and 0.02). The change in EoE Endoscopic Reference Score at M3 was also larger with mepolizumab. At M6, EEsAI decreased 18.3±18.1 points for mepo/mepo and 18.6±19.2 for pbo/mepo (p=0.85). The most common adverse events were injection-site reactions., Conclusions: Mepolizumab did not achieve the primary endpoint of improving dysphagia symptoms compared with placebo. While eosinophil counts and endoscopic severity improved with mepolizumab at 3 months, longer treatment did not yield additional improvement., Trial Registration Number: NCT03656380., Competing Interests: Competing interests: ESD has received research funding from Adare/Ellodi, Allakos, Arena, AstraZeneca, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Shire/Takeda; consulting fees from Abbott, Abbvie, Adare/ Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Landos, LucidDx, Morphic, Nexstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio; and educational grants from Allakos, Holoclara, Invea. IH has received research funding from Adare/Ellodi, Allakos, Arena, AstraZeneca, Meritage, Celgene/Receptos/BMS, Regeneron, Shire/Takeda; consulting fees from Adare/ Ellodi, Allakos, Amgen, Arena/Pfizer, Aslan, AstraZeneca, Celgene/Receptos/BMS, Celldex, EsoCap, Gossamer Bio, Nexstone Immunology, Parexel/Calyx, Phathom, Regeneron, Sanofi, Shire/Takeda. KAP has received research funding from AstraZeneca, Allakos, Adare, Regeneron-Sanofi, Revolo,; Speaker: AGA, Regeneron, Peerview, Takeda, Allakos, WebMD; unrestricted grant support from Allakos, Chobani; consulting or advisory board fees from AGA, Alladapt, AstraZeneca, Allakos, Bristol Meyers Squibb, Ellodi, Invea, Lucid, Nexstone, WebMD, Peerview, Regeneron, Revolo, Takeda, WebMD; and has equity in Nexeos Bio. The other authors report no relevant disclosures., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The atomization enthalpies of the U(VI) species UF 6 and the uranium oxyhalides UO 2 X 2 (X = F, Cl, Br, I, and At) were calculated using a composite relativistic Feller-Peterson-Dixon (FPD) approach based on scalar relativistic DKH3-CCSD(T) with extrapolations to the CBS limit. The inherent multideterminant nature of the U atom was mitigated by utilizing the singly charged atomic cation in all calculations with correction back to the neutral asymptote via the accurate ionization energy of the U atom. The effects of SO coupling were recovered using full 4-component CCSD(T) with contributions due to the Gaunt Hamiltonian calculated using Dirac-Hartree-Fock. The final atomization enthalpy for UF 6 (752.2 kcal/mol) was within 2.5 kcal/mol of the experimental value, but unfortunately the latter carries a ±2.4 kcal/mol uncertainty that is predominantly due to the experimental uncertainty in the formation enthalpy of the U atom. The analogous value for UO 2 F 2 (607.6 kcal/mol) was in nearly exact agreement with the experiment, but the latter has a stated experimental uncertainty of ±4.3 kcal/mol. The FPD atomization enthalpy for UO 2 Cl 2 (540.4 kcal/mol) was within the experimental error limit of ±5.5 kcal/mol. FPD atomization energies for the non-U-containing molecules (used for reaction enthalpies) H 2 O and HX (X = F, Cl, Br, I, and At) were within at most 0.3 kcal/mol of their experimental values where available. The FPD atomization enthalpies, together with FPD reaction enthalpies for two different reactions, were used to determine heats of formation for all species of this work, with estimated uncertainties of ±4 kcal/mol. The calculated heat of formation for UF 6 (-511.0 kcal/mol) is within 2.5 kcal/mol of the accurately known (±0.45 kcal/mol) experimental value.

Purpose: To learn how the highest-performing primary care practices manage change when implementing improvements to diabetes care delivery., Methods: We ranked a total of 330 primary care practices submitting practice management assessments and diabetes reports to the Understanding Infrastructure Transformation Effects on Diabetes study in 2017 and 2019 by Optimal Diabetes Care performance. We ranked practices from the top quartile by greatest annual improvement to capture dynamic change. Starting with the top performers, we interviewed practice leaders to identify their most effective strategies for managing change. Interview transcripts were qualitatively analyzed to identify change management strategies. Saturation occurred when no new strategies were identified over 2 consecutive interviews., Results: Ten of the top 13 practices agreed to interviews. We identified 199 key comments representing 48 key care management concepts. We also categorized concepts into 6 care management themes and 37 strategic approaches. We categorized strategic approaches into 13 distinct change management strategies. The most common strategies identified were (1) standardizing the care process, (2) performance awareness, (3) enhancing care teams, (4) health care organization participation, (5) improving reporting systems, (6) engaging staff and clinicians, (7) accountability for tasks, (8) engaging leadership, and (9) tracking change. Care management themes identified by most practices included proactive care, improving patient relationships, and previsit planning., Conclusions: Top-performing primary care practices identify a similar group of strategies as important for managing change during quality improvement activities. Practices involved in diabetes improvement activities, and perhaps other chronic conditions, should consider adopting these change management strategies., (© 2023 Annals of Family Medicine, Inc.)

A collaborative effort between experiment and theory toward elucidating the electronic and molecular structures of uranium-gold clusters is presented. Anion photoelectron spectra of UAu n - ( n = 3-7) were taken at the third (355 nm) and fourth (266 nm) harmonics of a Nd:YAG laser, as well as excimer (ArF 193 nm) photon energies, where the experimental adiabatic electron affinities and vertical detachment energies values were measured. Complementary first-principles calculations were subsequently carried out to corroborate experimentally determined electron detachment energies and to determine the geometry and electronic structure for each cluster. Except for the ring-like neutral isomer of UAu 6 where one unpaired electron is spread over the Au atoms, all other neutral and anionic UAu n clusters ( n = 3-7) were calculated to possess open-shell electrons with the unpaired electrons localized on the central U atom. The smaller clusters closely resemble the analogous UF n species, but significant deviations are seen starting with UAu 5 where a competition between U-Au and Au-Au bonding begins to become apparent. The UAu 6 system appears to mark a transition where Au-Au interactions begin to dominate, where both a ring-like and two heavily distorted octahedral structures around the central U atom are calculated to be nearly isoenergetic. With UAu 7 , only ring-like structures are calculated. Overall, the calculated electron detachment energies are in good agreement with the experimental values.

Dietary therapy for short- and long-term management of eosinophilic esophagitis is an effective yet poorly understood and underutilized treatment strategy. Despite several prospective trials demonstrating the efficacy of dietary therapies, successful clinical implementation is hampered by the need for a multidisciplinary approach including dietitian support and provider expertise. The availability of these resources is not readily available to most gastroenterologists. Without standardized guidance on starting or completing the diet for gastrointestinal providers and/or consulting dietitians, provider attitudes toward dietary therapy vary greatly depending on familiarity and knowledge gaps in using diet therapy. This review aims to summarize evidence in support of dietary therapy in eosinophilic esophagitis while providing guidance on initiation and implementation of dietary therapy for providers., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Genome editing with CRISPR-associated (Cas) proteins holds exceptional promise for "correcting" variants causing genetic disease. To realize this promise, off-target genomic changes cannot occur during the editing process. Here, we use whole genome sequencing to compare the genomes of 50 Cas9-edited founder mice to 28 untreated control mice to assess the occurrence of S. pyogenes Cas9-induced off-target mutagenesis. Computational analysis of whole-genome sequencing data detects 26 unique sequence variants at 23 predicted off-target sites for 18/163 guides used. While computationally detected variants are identified in 30% (15/50) of Cas9 gene-edited founder animals, only 38% (10/26) of the variants in 8/15 founders validate by Sanger sequencing. In vitro assays for Cas9 off-target activity identify only two unpredicted off-target sites present in genome sequencing data. In total, only 4.9% (8/163) of guides tested have detectable off-target activity, a rate of 0.2 Cas9 off-target mutations per founder analyzed. In comparison, we observe ~1,100 unique variants in each mouse regardless of genome exposure to Cas9 indicating off-target variants comprise a small fraction of genetic heterogeneity in Cas9-edited mice. These findings will inform future design and use of Cas9-edited animal models as well as provide context for evaluating off-target potential in genetically diverse patient populations., (© 2023. The Author(s).)

Ecological communities are increasingly subject to natural and human-induced additions of species, as species shift their ranges under climate change, are introduced for conservation and are unintentionally moved by humans. As such, decisions about how to manage ecosystems subject to species introductions and considering multiple management objectives need to be made. However, the impacts of gaining new species on ecological communities are difficult to predict due to uncertainty in introduced species characteristics, the novel interactions that will be produced by that species, and the recipient ecosystem structure. Drawing on ecological and conservation decision theory, we synthesise literature into a conceptual framework for species introduction decision-making based on ecological networks in high-uncertainty contexts. We demonstrate the application of this framework to a theoretical decision surrounding assisted migration considering both biodiversity and ecosystem service objectives. We show that this framework can be used to evaluate trade-offs between outcomes, predict worst-case scenarios, suggest when one should collect additional data, and allow for improving knowledge of the system over time., (© 2023 John Wiley & Sons Ltd.)

Description: The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update is to review the available evidence and expert advice regarding the clinical management of patients with suspected extraesophageal gastroesophageal reflux disease., Methods: This article provides practical advice based on the available published evidence including that identified from recently published reviews from leading investigators in the field, prospective and population studies, clinical trials, and recent clinical guidelines and technical reviews. This best practice document is not based on a formal systematic review. The best practice advice as presented in this document applies to patients with symptoms or conditions suspected to be related to extraesophageal reflux (EER). This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPUC and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. BEST PRACTICE ADVICE 1: Gastroenterologists should be aware of potential extraesophageal manifestations of gastroesophageal reflux disease (GERD) and should inquire about such disorders including laryngitis, chronic cough, asthma, and dental erosions in GERD patients to determine whether GERD may be a contributing factor to these conditions. BEST PRACTICE ADVICE 2: Development of a multidisciplinary approach to extraesophageal (EER) manifestations is an important consideration because the conditions are often multifactorial, requiring input from non-gastroenterology (GI) specialties. Results from diagnostic testing (ie, bronchoscopy, thoracic imaging, laryngoscopy, etc) from non-GI disciplines should be taken into consideration when gastroesophageal reflux (GER) is considered as a cause for extraesophageal symptoms. BEST PRACTICE ADVICE 3: Currently, there is no single diagnostic tool that can conclusively identify GER as the cause of EER symptoms. Determination of the contribution of GER to EER symptoms should be based on the global clinical impression derived from patients' symptoms, response to GER therapy, and results of endoscopy and reflux testing. BEST PRACTICE ADVICE 4: Consideration should be given toward diagnostic testing for reflux before initiation of proton pump inhibitor (PPI) therapy in patients with potential extraesophageal manifestations of GERD, but without typical GERD symptoms. Initial single-dose PPI trial, titrating up to twice daily in those with typical GERD symptoms, is reasonable. BEST PRACTICE ADVICE 5: Symptom improvement of EER manifestations while on PPI therapy may result from mechanisms of action other than acid suppression and should not be regarded as confirmation for GERD. BEST PRACTICE ADVICE 6: In patients with suspected extraesophageal manifestation of GERD who have failed one trial (up to 12 weeks) of PPI therapy, one should consider objective testing for pathologic GER, because additional trials of different PPIs are low yield. BEST PRACTICE ADVICE 7: Initial testing to evaluate for reflux should be tailored to patients' clinical presentation and can include upper endoscopy and ambulatory reflux monitoring studies of acid suppressive therapy. BEST PRACTICE ADVICE 8: Testing can be considered for those with an established objective diagnosis of GERD who do not respond to high doses of acid suppression. Testing can include pH-impedance monitoring while on acid suppression to evaluate the role of ongoing acid or non-acid reflux. BEST PRACTICE ADVICE 9: Alternative treatment methods to acid suppressive therapy (eg, lifestyle modifications, alginate-containing antacids, external upper esophageal sphincter compression device, cognitive-behavioral therapy, neuromodulators) may serve a role in management of EER symptoms. BEST PRACTICE ADVICE 10: Shared decision-making should be performed before referral for anti-reflux surgery for EER when the patient has clear, objectively defined evidence of GERD. However, a lack of response to PPI therapy predicts lack of response to anti-reflux surgery and should be incorporated into the decision process., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Humans use predictions to improve speech perception, especially in noisy environments. Here we use 7-T functional MRI (fMRI) to decode brain representations of written phonological predictions and degraded speech signals in healthy humans and people with selective frontal neurodegeneration (non-fluent variant primary progressive aphasia [nfvPPA]). Multivariate analyses of item-specific patterns of neural activation indicate dissimilar representations of verified and violated predictions in left inferior frontal gyrus, suggestive of processing by distinct neural populations. In contrast, precentral gyrus represents a combination of phonological information and weighted prediction error. In the presence of intact temporal cortex, frontal neurodegeneration results in inflexible predictions. This manifests neurally as a failure to suppress incorrect predictions in anterior superior temporal gyrus and reduced stability of phonological representations in precentral gyrus. We propose a tripartite speech perception network in which inferior frontal gyrus supports prediction reconciliation in echoic memory, and precentral gyrus invokes a motor model to instantiate and refine perceptual predictions for speech., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Empirical elimination diets are effective for achieving histological remission in eosinophilic oesophagitis, but randomised trials comparing diet therapies are lacking. We aimed to compare a six-food elimination diet (6FED) with a one-food elimination diet (1FED) for the treatment of adults with eosinophilic oesophagitis., Methods: We conducted a multicentre, randomised, open-label trial across ten sites of the Consortium of Eosinophilic Gastrointestinal Disease Researchers in the USA. Adults aged 18-60 years with active, symptomatic eosinophilic oesophagitis were centrally randomly allocated (1:1; block size of four) to 1FED (animal milk) or 6FED (animal milk, wheat, egg, soy, fish and shellfish, and peanut and tree nuts) for 6 weeks. Randomisation was stratified by age, enrolling site, and gender. The primary endpoint was the proportion of patients with histological remission (peak oesophageal count <15 eosinophils per high-power field [eos/hpf]). Key secondary endpoints were the proportions with complete histological remission (peak count ≤1 eos/hpf) and partial remission (peak counts ≤10 and ≤6 eos/hpf) and changes from baseline in peak eosinophil count and scores on the Eosinophilic Esophagitis Histology Scoring System (EoEHSS), Eosinophilic Esophagitis Endoscopic Reference Score (EREFS), Eosinophilic Esophagitis Activity Index (EEsAI), and quality of life (Adult Eosinophilic Esophagitis Quality-of-Life and Patient Reported Outcome Measurement Information System Global Health questionnaires). Individuals without histological response to 1FED could proceed to 6FED, and those without histological response to 6FED could proceed to swallowed topical fluticasone propionate 880 μg twice per day (with unrestricted diet), for 6 weeks. Histological remission after switching therapy was assessed as a secondary endpoint. Efficacy and safety analyses were done in the intention-to-treat (ITT) population. This trial is registered on ClinicalTrials.gov, NCT02778867, and is completed., Findings: Between May 23, 2016, and March 6, 2019, 129 patients (70 [54%] men and 59 [46%] women; mean age 37·0 years [SD 10·3]) were enrolled, randomly assigned to 1FED (n=67) or 6FED (n=62), and included in the ITT population. At 6 weeks, 25 (40%) of 62 patients in the 6FED group had histological remission compared with 23 (34%) of 67 in the 1FED group (difference 6% [95% CI -11 to 23]; p=0·58). We found no significant difference between the groups at stricter thresholds for partial remission (≤10 eos/hpf, difference 7% [-9 to 24], p=0·46; ≤6 eos/hpf, 14% [-0 to 29], p=0·069); the proportion with complete remission was significantly higher in the 6FED group than in the 1FED group (difference 13% [2 to 25]; p=0·031). Peak eosinophil counts decreased in both groups (geometric mean ratio 0·72 [0·43 to 1·20]; p=0·21). For 6FED versus 1FED, mean changes from baseline in EoEHSS (-0·23 vs -0·15; difference -0·08 [-0·21 to 0·05]; p=0·23), EREFS (-1·0 vs -0·6; difference -0·4 [-1·1 to 0·3]; p=0·28), and EEsAI (-8·2 vs -3·0; difference -5·2 [-11·2 to 0·8]; p=0·091) were not significantly different. Changes in quality-of-life scores were small and similar between the groups. No adverse event was observed in more than 5% of patients in either diet group. For patients without histological response to 1FED who proceeded to 6FED, nine (43%) of 21 reached histological remission; for patients without histological response to 6FED who proceeded to fluticasone propionate, nine (82%) of 11 reached histological remission., Interpretation: Histological remission rates and improvements in histological and endoscopic features were similar after 1FED and 6FED in adults with eosinophilic oesophagitis. 6FED had efficacy in just less than half of 1FED non-responders and steroids had efficacy in most 6FED non-responders. Our findings indicate that eliminating animal milk alone is an acceptable initial dietary therapy for eosinophilic oesophagitis., Funding: US National Institutes of Health., Competing Interests: Declaration of interests NG receives royalties from UpToDate; is a consultant for Allakos, Regeneron-Sanofi, AstraZeneca, AbbVie, Takeda, Knopp, Bristol Meyers Squibb, and Nutricia; and has received payment or honoraria for speaker's bureaus for Takeda and Regeneron-Sanofi. ESD has received research support from Ellodi (formerly Adare), Allakos, Arena, AstraZeneca, GlaxoSmithKline, Meritage, Miraca, Nutricia, Celgene (formerly Receptos and a subsidiary of Bristol Myers Squibb), Regeneron, Revolo, and Shire (a subsidiary of Takeda); is a consultant for Abbott, AbbVie, Ellodi, Aimmune, Akesobio, Allakos, Amgen, Arena, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene, Celldex, Eli Lilly, EsoCap, GlaxoSmithKline, Gossamer Bio, Invea, Landos, Lucid Diagnostics, Morphic, Nutricia, Calyx (formerly Parexel), Phathom, Regeneron, Revolo, Alimentiv (formerly Robarts), Salix, Sanofi, Shire, and Target RWE; and has education grants with Allakos, Banner, and Holoclara. DAK has received consulting fees and payments for presentations from Celgene; has served on a data and safety monitoring board at the University of North Carolina; and serves on the governing board of the American Gastroenterological Association. JPA has received research support from Cures Within Reach and Celgene; has received payment or honoraria for lectures from Takeda; and has served on a data and safety monitoring board for Octapharma USA. SSA has received research support from Implicit Biosciences and the Campaign Urging Research for Eosinophilic Disease (CURED) Foundation; has received consulting fees from Bristol Meyers Squibb, Regeneron-Sanofi, and AstraZeneca; has received payment for presentations or events from Regeneron-Sanofi; and receives patent royalties and is co-inventor of oral viscous budesonide, patented by University of California San Diego and licensed by Shire. KEC is employed by and has an equity interest in Alnylam. MC has received consulting fees from Regeneron, Allakos, Ellodi, Shire, AstraZeneca, Sanofi, Bristol Myers Squibb, Phathom; has received research support from Regeneron, Allakos, Shire, AstraZeneca, Ellodi, and Danone; and holds leadership roles in the American Partnership for Eosinophilic Disorders (APFED) and the American Academy of Allergy, Asthma and Immunology (AAAAI). AC has received research support from Aimmune and DBV Technologies; has served on a data and safety monitoring board for Regeneron, Sanofi, AstraZeneca, and DBV Technologies; and holds leadership roles in the AAAAI, European Academy of Allergy and Clinical Immunology, and American College of Allergy, Asthma and Immunology. MHC is a consultant for Allakos, AstraZeneca, Bristol Myers Squibb, Esocap, GlaxoSmithKline, Shire, Regeneron, Celgene, Sanofi, and Ellodi; has received research funding from Shire, Regeneron, Celgene, and AstraZeneca; holds leadership roles in the APFED, CURED Foundation, and The International Gastrointestinal Eosinophil Researchers; and has received travel support from Regeneron and Celgene. GWF is a consultant for Ellodi, Allakos, Celgene, Lucid, Nexstone, Phathom, Regeneron, Bristol Myers Squibb, Upstream Bio, and Shire; has served on a data and safety monitoring board for Revolo; has a leadership role in the International Society for Diseases of the Esophagus; and has equity in Bristol Myers Squibb. SKG has received research support from Allakos, Ellodi, and AstraZeneca; receives royalties from UpToDate; is a consultant for Ellodi, Bristol Myers Squibb, QOL Medical, Takeda, and Viaskin; has received payment from Medscape and PeerView Institute for Medical Education; has served on a data and safety monitoring board for Bristol Myers Squibb; and has a leadership role in the Association of Pediatric Gastroenterology and Nutrition Nurses, American Gastroenterological Association, and Journal of Pediatric Gastroenterology and Nutrition. JL has received research funding AstraZeneca, Allakos, Takeda, Provention Bio, Ellodi, Arena Pharmaceuticals, GI Health Foundation, Ellodi, ALK Abelló, Revolo Biotherapeutics, Bristol Myers Squibb, Regeneron, Phathom Pharmaceuticals; has received consulting fees from Guidepoint, Takeda, Third Bridge, Boston Consulting Group, AbbVie, Sanofi, Huron Consulting Services, Ribon Therapeutics, Tegus, Slingshot, Cowen, and AstraZeneca; has received speaker payments from Regeneron, Sanofi, AGA Carney, AGA Tufts, and Maine Medical Center; has received payment for expert testimony for Devine, Millimet and Branch Professional Education; and has a leadership role with Kwong Kow Chinese School. IH has received consulting fees from Ellodi, AstraZeneca, Arena, Allakos, Calyx (formerly Parexel), Celgene, Celldex, Regeneron, Esocap, Gossamer Bio, Lilly, Phathom, Sanofi, and Shire; has received research funding Meritage, Ellodi, Celgene, Regeneron-Sanofi, and Shire; and participated in a speaker bureau for Regeneron and Sanofi. LJM has received honoraria from Akron's Children's Hospital and is co-inventor on a patent for Cysteamine. VAM has received consulting fees from Shire, Allakos, Regeneron, and Sanofi; and has received research funding and support from Meritage and Shire. KAP has received research support from Allakos, Ellodi, AstraZeneca, Chobani, Regeneron-Sanofi, and Revolo; is a consultant for AGA, AstraZeneca, Allakos, Bristol Meyers Squibb, Ellodi, Invea, Lucid, Nexstone, WebMD, Peerview, Regeneron, Revolo, and Takeda; has received speaker payments from AGA, Regeneron, Peerview, Takeda, Allakos, and WebMD; has served on a data and safety monitoring board for Alladapt; and has a patent and stock options with Nexeos Bio. JMS is a consultant for Regeneron, Sanofi, DBV Technology, Ready Set Food, and Kaleo; has received research support from Regeneron-Sanofi, Food Allergy Research and Education, and Novartis; and has received royalties from UpToDate. GTF is Chief Medical Officer of EnteroTrack; and is a consultant for Shire. MER is a consultant for AstraZeneca, Bristol Myers Squibb, Regeneron-Sanofi, Revolo Biotherapeutics, Celldex, Nexstone One, and Guidepoint; has received research support from AstraZeneca, Regeneron-Sanofi, GlaxoSmithKline, the CURED Foundation, Food Allergy Fund, and a US–Israel Binational Grant (number 2019016); has equity interest in PulmOne Therapeutics, Spoon Guru, ClostraBio, Serpin Pharm, Celldex, Nextstone One, and Allakos; receives royalties from Ception Therapeutics (for reslizumab), Mapi Research Trust (for the Pediatric Eosinophilic Esophagitis Symptom Score version 2) and UpToDate; has received equipment from Phadia; has a leadership role in the International Eosinophil Society; has received payment for expert testimony from Tucker Ellis; and is an inventor on a patent (US patent 9,345,763) owned by Cincinnati Children's Hospital Medical Center. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Primary cilia are nearly ubiquitous organelles that transduce molecular and mechanical signals. Although the basic structure of the cilium and the cadre of genes that contribute to ciliary formation and function (the ciliome) are believed to be evolutionarily conserved, the presentation of ciliopathies with narrow, tissue-specific phenotypes and distinct molecular readouts suggests that an unappreciated heterogeneity exists within this organelle. Here, we provide a searchable transcriptomic resource for a curated primary ciliome, detailing various subgroups of differentially expressed genes within the ciliome that display tissue and temporal specificity. Genes within the differentially expressed ciliome exhibited a lower level of functional constraint across species, suggesting organism and cell-specific function adaptation. The biological relevance of ciliary heterogeneity was functionally validated by using Cas9 gene-editing to disrupt ciliary genes that displayed dynamic gene expression profiles during osteogenic differentiation of multipotent neural crest cells. Collectively, this novel primary cilia-focused resource will allow researchers to explore longstanding questions related to how tissue and cell-type specific functions and ciliary heterogeneity may contribute to the range of phenotypes associated with ciliopathies., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Verbal fluency is widely used as a clinical test, but its utility in differentiating between neurodegenerative dementias and progressive aphasias, and from healthy controls, remains unclear. We assessed whether various measures of fluency performance could differentiate between Alzheimer's disease, behavioural variant of frontotemporal dementia, non-fluent and semantic variants of primary progressive aphasia, progressive supranuclear palsy, corticobasal syndrome and healthy controls. Category and letter fluency tasks were administered to 33 controls and 139 patients at their baseline clinical visit. We assessed group differences for total number of words produced, psycholinguistic word properties and associations between production order and exemplar psycholinguistic properties. Receiver operating characteristic curves determined which measure could best discriminate patient groups and controls. The total word count distinguished controls from all patient groups, but neither this measure nor the word properties differentiated the patient groups. Receiver operating characteristic curves revealed that, when comparing controls to patients, the strongest discriminators were total word count followed by word frequency. Word frequency was the strongest discriminator for semantic variant of primary progressive aphasia versus other groups. Fluency word counts were associated with global severity as measured by Addenbrooke's Cognitive Examination Revised. Verbal fluency is an efficient test for assessing global brain-cognitive health but has limited utility in differentiating between cognitively and anatomically disparate patient groups. This outcome is consistent with the fact that verbal fluency requires many different aspects of higher cognition and language., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The impact of complete basis set extrapolation schemes (CBS), diffuse functions, and tight weighted-core functions on enthalpies of formation predicted via the DLPNO-CCSD(T1) reduced Feller-Peterson-Dixon approach has been examined for neutral H,C,O-compounds. All tested three-point (TZ/QZ/5Z) extrapolation schemes result in mean unsigned deviation (MUD) below 2 kJ mol -1 relative to the experiment. The two-point QZ/5Z and TZ/QZ CBS 1 / l max 3 extrapolation schemes are inferior to their inverse power counterpart ( 1 / l max + 1 / 2 4 ) by 1.3 and 4.3 kJ mol -1 . The CBS extrapolated frozen core atomization energies are insensitive (within 1 kJ mol -1 ) to augmentation of the basis set with tight weighted core functions. The core-valence correlation effects converge already at triple-ζ, although double-ζ/triple-ζ CBS extrapolation performs better and is recommended. The effect of diffuse function augmentation converges slowly, and cannot be reproduced with double- ζ or triple- ζ calculations as these are plagued with basis set superposition and incompleteness errors., (© 2022 Wiley Periodicals LLC.)

Introduction: There are limited data on the familial risk of distal eosinophilic gastrointestinal diseases (EGIDs) in patients with eosinophilic esophagitis (EoE). We analyzed the risk of eosinophilic gastritis/gastroenteritis (EG/EGE) and eosinophilic colitis (EC) as forms of distal EGIDs using International Disease Classification-9/10 codes in subjects with EoE and their relatives., Methods: The Utah Population Database is a resource that links genealogy information and medical records in Utah. We identified EGIDs in probands and their first-degree (FDRs), second-degree (SDRs), and third-degree (TDRs) relatives in the Utah Population Database. Relative risk and 95% confidence intervals were estimated. All individuals with inflammatory bowel disorder were eliminated to avoid misdiagnosis with EGIDs., Results: We included 8,455 subjects with EoE, 396 with EG/EGE, and 172 with EC. Probands with EoE were at increased risk of EG/EGE and EC. Risks of EG/EGE were increased among FDRs and SDRs of probands with EoE , even without concomitant EoE in the relatives. Increased risk of EG/EGE in FDRs and SDRs was also present for EoE probands without EG/EGE or EC. We observed no isolated familial aggregation of EG/EGE after excluding cases with comorbid EoE. EC probands without EoE were at increased risk of EG/EGE, but no evidence of familial risk of EC was observed., Discussion: The relative risk of EG/EGE is significant among relatives of patients with EoE, suggesting that shared genetic factors exist among these EGIDs. EG/EGE and EC showed limited familial clustering, although sample sizes were small., (Copyright © 2022 by The American College of Gastroenterology.)

The thermochemistry of halocarbon species containing iodine and bromine is examined through an extensive interplay between new Feller-Peterson-Dixon (FPD) style composite methods and a detailed analysis of all available experimental and theoretical determinations using the thermochemical network that underlies the Active Thermochemical Tables (ATcT). From the computational viewpoint, a slower convergence of the components of composite thermochemistry methods is observed relative to species that solely contain first row elements, leading to a higher computational expense for achieving comparable levels of accuracy. Potential systematic sources of computational uncertainty are investigated, and, not surprisingly, spin-orbit coupling is found to be a critical component, particularly for iodine containing molecular species. The ATcT analysis of available experimental and theoretical determinations indicates that prior theoretical determinations have significantly larger uncertainties than originally reported, particularly in cases where molecular spin-orbit effects were ignored. Accurate and reliable heats of formation are reported for 38 halogen containing systems, based on combining the current computations with previous experimental and theoretical work via the ATcT approach.

Background: Exposure to prescription opioids during adolescence is associated with an increased risk of future opioid misuse. The pervasive and growing impact of the opioid epidemic requires evidence-based, co-designed interventions targeted at adolescents. MedSMA℞T Families is an intervention tailored to educate adolescents and their families about opioid misuse prevention and consists of two parts: the MedSMA℞T: Adventures in PharmaCity videogame and the family medication safety plan (FMSP)., Objective: This study sought to explore pharmacists' perceptions of using the family medication safety plan to facilitate opioid education among parents and their adolescents. The purpose of this project was to also gather information for iterative adaptations to improve implementation and dissemination of the FMSP in pharmacy settings., Methods: Pharmacists were recruited from Pharmacy Practice Enhancement and Action Research Link (PearlRx) and the Pharmacy Society of Wisconsin (PSW). Twenty-one pharmacist interviews were conducted between September 2021 and March 2022. Consenting pharmacists reviewed the FMSP. Then, semi-structured interviews were conducted, recorded, and transcribed. Inductive thematic analyses were performed using NVivo software., Results: Four prevalent themes emerged: (1) the purpose of FMSP as a communication tool, (2) instructions to clarify how to use FMSP, (3) barriers to using FMSP, and (4) suggestions to improve FMSP format. Most pharmacists described the FMSP as a tool to encourage interactive opioid conversations between adolescents, families, and pharmacists. Pharmacists suggested creating multiple customizable formats and incorporating instructions on how to use the FMSP., Conclusions: Pharmacists noted that the FMSP was an interactive and engaging communication tool to tailor opioid consultations with adolescents and their families. Patients might use the FMSP as a visual cue to help think of what question(s) they should ask pharmacists. Pharmacists stated that the FMSP could facilitate tailored opioid safety communication and medication consultations. Insights will inform future medication misuse prevention interventions as well as adaptation.

Purpose: To learn whether the COVID-19 pandemic's disruptions and associated reduced health outcomes for people with chronic conditions might have been caused by a decrease in care management processes (CMPs) in primary care clinics METHODS: Longitudinal cohort design with repeated survey-based measures of CMPs from 2017, 2019, and 2021 in 269 primary care clinics in Minnesota., Results: There were only small differences in organizational characteristics and no differences in overall CMPs between the 269 clinics analyzed and the 287 that only completed surveys in 1 or 2 years. Overall CMP scores rose by similar amounts (1.6% and 2.1%) from 2017 to 2019 and from 2019 to 2021. In 2021, CMP scores were lower in small medical groups than in large medical groups in 2017 (66.1% vs 78.5%, P <.001), a similar difference to that in 2017. Care management process scores were also lower in clinics in urban areas compared with rural areas (73.9% vs 79.0%, P <.001), but overall scores in all subgroups were higher in 2021 than in 2017. This improvement occurred despite reports from 55% of clinic leaders that the pandemic had been very or extremely disruptive., Conclusions: Although quite disrupted by the pandemic, care management processes for chronic disease care in these resilient primary care clinics actually increased from 2019 to 2021, at least in clinics that were part of large organizations. However, that was not true for clinics from smaller groups and perhaps for other areas of care., (© 2023 Annals of Family Medicine, Inc.)

A combination of high-level ab initio calculations and anion photoelectron detachment (PD) measurements is reported for the UC, UC - , and UC + molecules. To better compare the theoretical values with the experimental photoelectron spectrum (PES), a value of 1.493 eV for the adiabatic electron affinity (AEA) of UC was calculated at the Feller-Peterson-Dixon (FPD) level. The lowest vertical detachment energy (VDE) is predicted to be 1.500 eV compared to the experimental value of 1.487 ± 0.035 eV. A shoulder to lower energy in the experimental PD spectrum with the 355 nm laser can be assigned to a combination of low-lying excited states of UC - and excited vibrational states. The VDEs calculated for the low-lying excited electronic states of UC at the SO-CASPT2 level are consistent with the observed additional electron binding energies at 1.990, 2.112, 2.316, and 3.760 eV. Potential energy curves for the Ω states and the associated spectroscopic properties are also reported. Compared to UN and UN + , the bond dissociation energy (BDE) of UC (411.3 kJ/mol) is predicted to be considerably lower. The natural bond orbitals (NBO) calculations show that the UC 0/+/- molecules have a bond order of 2.5 with their ground-state configuration arising from changes in the oxidation state of the U atom in terms of the 7s orbital occupation: UC (5f 2 7s 1 ), UC - (5f 2 7s 2 ), and UC + (5f 2 7s 0 ). The behavior of the UN and UC sequence of molecules and anions differs from the corresponding sequences for UO and UF.

Introduction: Despite effective dietary treatments, physicians prefer medications for eosinophilic esophagitis (EoE)., Methods: We conducted a web-based survey of providers to assess the perceived effectiveness, practice patterns, and barriers to EoE dietary therapy., Results: Providers view diet as the least effective treatment. The greatest barrier was the belief that patients are disinterested and unlikely to adhere (58%). With less access to dietitians (56%), nonacademic providers often manage diets without dietitian guidance (41%)., Discussion: Given high patient acceptance for diets and multiple treatment options for EoE, clinicians need evidence-based knowledge on EoE diets, access to dietitians, and awareness of patient preferences., (Copyright © 2022 by The American College of Gastroenterology.)

Objective: To learn how high performing primary care practices organized care for patients with diabetes during the initial months of the COVID-19 pandemic., Participants and Methods: Semi-structured interviews were conducted between August 10 and December 10, 2020 with 16 leaders from 11 practices that had top quartile performance measures for diabetes outcomes pre-COVID. Each clinic had completed a similar interview and a survey about the existence of care management systems associated with quality outcomes before the pandemic. Transcript analysis utilized a theoretical thematic analysis at the semantic level., Results: The pandemic disrupted the primary care practices' operations and processes considered important for quality prior to the pandemic, particularly clinic reliance on proactive patient care. Safety concerns resulted from the shift to virtual visits, which produced documentation gaps and led practices to reorder their use of proactive patient care processes. Informal interactions with patients also declined. These practices' challenges were mitigated by technical, informational and operational help from the larger organizations of which they were a part. Care management processes had to accommodate both in-person and virtual visits., Conclusion: These high performing practices demonstrated an ability to adapt their use of proactive patient care processes in pursuing quality outcomes for patients with diabetes during the pandemic. Continued clinic transformation and improvements in quality within primary care depend on the ability to restructure the responsibilities of care team members and their interactions with patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Eder et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

While there are physiologic differences in lipid metabolism in men and women, pharmacologic therapy is very effective in both with similar management strategies recommended in the current guidelines for the management of dyslipidemia. Despite similar guidelines for treatment, studies have shown that women have worse control of dyslipidemia than their male counterparts. This may stem from multiple contributing factors including underestimation of cardiovascular disease risk in women, decreased prescription and utilization of lipid-lowering therapies, decreased medication adherence, and higher risk of statin intolerance, all of which may contribute to lower attainment of lipid targets. Furthermore, heart disease is the leading cause of mortality in women, with heart disease noted an average of 7-10 years later than in men. This has historically led to the misperception that women are protected from heart disease and can be treated less aggressively. In fact, traditional risk factors for atherosclerotic cardiovascular disease often impact risk in women to a greater extent than they do in men. Unique risk factors such as pregnancy-related disorders also contribute to the level of risk and therefore warrant consideration in risk stratification. This review summarizes the efficacy of contemporary lipid-lowering therapies in women versus men and discusses the challenges that arise with lipid management in women along with potential ways to tackle these obstacles., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

The results of calculations of the properties of the anion UN - including electron detachment are described, which further expand our knowledge of this diatomic molecule. High-level electronic structure calculations were conducted for the UN and UN - diatomic molecules and compared to photoelectron spectroscopy measurements. The low-lying Ω states were obtained using multireference CASPT2 including spin-orbit effects up to ∼20,000 cm -1 . At the Feller-Peterson-Dixon (FPD) level, the adiabatic electron affinity (AEA) of UN is estimated to be 1.402 eV and the vertical detachment energy (VDE) is 1.423 eV. The assignment of the UN excited states shows good agreement with the experimental results with a VDE of 1.424 eV. An Ω = 4 ground state was obtained for UN - which is mainly associated with the 3 H ΛS state. Thermochemical calculations estimate a bond dissociation energy (BDE) for UN - (U - + N) of 665.9 kJ/mol, ∼15% larger than that of UN and UN + . The NBO analysis reveals U-N triple bonds for the UN, UN - , and UN + species.

Background & Aims: Substantial heterogeneity in terminology used for eosinophilic gastrointestinal diseases (EGIDs), particularly the catchall term "eosinophilic gastroenteritis," limits clinical and research advances. We aimed to achieve an international consensus for standardized EGID nomenclature., Methods: This consensus process utilized Delphi methodology. An initial naming framework was proposed and refined in iterative fashion, then assessed in a first round of Delphi voting. Results were discussed in 2 consensus meetings, and the framework was updated and reassessed in a second Delphi vote, with a 70% threshold set for agreement., Results: Of 91 experts participating, 85 (93%) completed the first and 82 (90%) completed the second Delphi surveys. Consensus was reached on all but 2 statements. "EGID" was the preferred umbrella term for disorders of gastrointestinal (GI) tract eosinophilic inflammation in the absence of secondary causes (100% agreement). Involved GI tract segments will be named specifically and use an "Eo" abbreviation convention: eosinophilic gastritis (now abbreviated EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). The term "eosinophilic gastroenteritis" is no longer preferred as the overall name (96% agreement). When &gt;2 GI tract areas are involved, the name should reflect all of the involved areas., Conclusions: This international process resulted in consensus for updated EGID nomenclature for both clinical and research use. EGID will be the umbrella term, rather than "eosinophilic gastroenteritis," and specific naming conventions by location of GI tract involvement are recommended. As more data are developed, this framework can be updated to reflect best practices and the underlying science., (Copyright © 2022. Published by Elsevier Inc.)

Background: Eosinophilic oesophagitis (EoE) is associated with elevated IgG4 in oesophageal tissue and serum. Previously, we showed brush-collected oesophageal secretions of EoE patients contained food antigen-specific antibodies IgA and IgG4. It is unknown whether other food-specific antibodies are present along the surface of the oesophagus in EoE., Aim: To identify whether immunoglobulins other than IgG4 and food-specific antibodies are elevated along the oesophageal mucosal surface in oesophageal secretions in EoE patients METHODS: Concentrations of total IgA, IgG1, IgG2, IgG3, IgG4, IgM and IgE were measured in oesophageal secretions from patients with active (n = 19) and inactive EoE (n = 9), and non-EoE controls (n = 10). Food-specific antibodies were measured using beads coupled to protein components from dairy, wheat and egg. Total immunoglobulin and cytokine and chemokine concentrations were measured in serum, saliva and oesophageal secretions of four patients with active EoE., Results: Oesophageal secretions have a unique immune profile. Patients with active EoE had elevated IgG2, IgG4 and IgM concentrations in oesophageal secretions compared to those with inactive EoE. Food-specific IgG1, IgG2, IgG4 and IgM were significantly increased in patients with active EoE compared to inactive EoE and non-EoE patients. Furthermore, active patients with a known dairy trigger display higher dairy-specific IgG1, IgG2, IgG4, IgM, IgA and IgE., Conclusions: There is a distinct localised profile of immunoglobulins and food-specific antibodies found within oesophageal secretions in EoE. These findings expand our knowledge about the currently identified immune responses in EoE and suggest possible roles for multiple immunoglobulins and food-specific antibodies in the pathophysiology of EoE., (© 2022 John Wiley & Sons Ltd.)

Endoscopy plays a critical role in caring for and evaluating the patient with eosinophilic esophagitis (EoE). Endoscopy is essential for diagnosis, assessment of response to therapy, treatment of esophageal strictures, and ongoing monitoring of patients in histologic remission. To date, less-invasive testing for identifying or grading EoE severity has not been established, whereas diagnostic endoscopy as integral to both remains the criterion standard. Therapeutic endoscopy in patients with adverse events of EoE may also be required. In particular, dilation may be essential to treat and attenuate progression of the disease in select patients to minimize further fibrosis and stricture formation. Using a modified Delphi consensus process, a group of 20 expert clinicians and investigators in EoE were assembled to provide guidance for the use of endoscopy in EoE. Through an iterative process, the group achieved consensus on 20 statements yielding comprehensive advice on tissue-sampling standards, gross assessment of disease activity, use and performance of endoscopic dilation, and monitoring of disease, despite an absence of high-quality evidence. Key areas of controversy were identified when discussions yielded an inability to reach agreement on the merit of a statement. We expect that with ongoing research, higher-quality evidence will be obtained to enable creation of a guideline for these issues. We further anticipate that forthcoming expert-generated and agreed-on statements will provide valuable practice advice on the role and use of endoscopy in patients with EoE., (Copyright © 2022 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Objective: Eosinophils are hallmarks in allergic type 2 inflammation and are known to release cytotoxic granule proteins that contribute to inflammation. Eosinophils develop in the bone marrow from hematopoietic stem cells and once mature, have a limited lifespan in culture, making them difficult to study ex vivo . IL-33 has increasingly been shown as a key regulator of type 2 inflammation via signaling through its receptor, ST2. The present study was conducted to detail a method of eosinophil differentiation from hematopoietic stem cells and determine the response to IL-33., Methods: CD34+ and CD14+ cells were isolated from donor apheresis cones and differentiated into eosinophils or macrophage controls, respectively. Morphologic, transcriptional and protein analyses were performed to validate this method of eosinophil differentiation. The effect of IL-33 on differentiated eosinophils was assessed using qPCR, immunofluorescence, and multiplex cytokine array., Results: CD34 differentiated eosinophils appear morphologically similar by H&E and express eosinophil peroxidase (EPX) protein as well as the conventional eosinophil transcripts EPX , CLC , and MBP . In addition, differentiated eosinophils expressed both isoforms of the IL-33 receptor, ST2L and s ST2 throughout the differentiation process. Transcript levels of both IL-33 receptors were up-regulated by treatment with IL-33 at earlier timepoints in the differentiation. These cells also expressed IL-4 and IL-13 mRNA which were up-regulated by IL-33 as well. Notably, IL-13 expression was significantly higher with IL-33 treatment compared to media control at every timepoint measured. IL-33 significantly increased cellular secretion of IL-13 protein at most timepoints throughout differentiation. IL-8, LIF, CCL1, CCL5, CCL7, and CCL8 were also significantly secreted after IL-33 stimulation., Conclusions: Our findings suggest that CD34 differentiated eosinophils are morphologically and phenotypically similar to peripheral eosinophils. The release of specific cytokines in direct response to IL-33 may contribute to the pathogenesis of type 2 inflammation and facilitates new avenues for studying eosinophils as effector cells in vitro ., Competing Interests: AU does not have any conflicts related to this work but serves on the medical advisory board for Sanofi-Genzyme. MD receives research support from Novartis and Eli Lilly, consulting fees from Partner Therapeutics, Tillotts Pharma, ORIC Pharmaceuticals, AzurRx, SQZ, Moderna, Aditum, and Mallinckrodt, and is a member of the Scientific Advisory Board for Neoleukin Therapeutics. SD reports no conflicts of interest related to this study, but has received research support from Novartis, BMS, Genocea, and Eli Lilly, is a co-founder and SAB member for Kojin, and received consulting fees from GSK. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Uchida, Ro, Qiang, Peterson, Round, Dougan and Dougan.)

Background: Gastric intestinal metaplasia (GIM) is a premalignant gastric mucosal change that is often incidentally detected during esophagogastroduodenoscopy (EGD). Despite the established higher risk of gastric cancer associated with GIM, the incidence, prevalence, and outcomes data for GIM are limited in the United States (US), and practice patterns are highly variable., Objectives: Our primary objectives were to accurately identify incident histology-confirmed GIM cases and determine patient characteristics, endoscopy findings, Helicobacter pylori (HP) detection, and eradication treatment outcomes, as well as surveillance and follow-up recommendations., Design: We conducted a retrospective cohort study using administrative data., Methods: We first developed and validated a rule-based natural language processing tool to identify the patients with GIM on gastrointestinal pathology reports between 2011 and 2016. We then performed a manual chart review of all EGD procedures and associated pathology notes to confirm cases and obtain clinically relevant data., Results: In all, 414 patients with an index diagnosis of GIM were confirmed (prevalence = 2.5% of patients undergoing any EGD). A majority (52.4%) of patients were non-Hispanic white. The most common indication for EGD was abdominal pain (46.9%). A majority (55%) did not receive specific follow-up recommendations or were asked to see their primary care provider. HP testing was documented in 86% of patients, and detected in 94 patients (prevalence = 26.4%). Treatment was documented in 94.7% of cases, and eradication confirmed in only 34.8% of these cases., Conclusion: A large group of US patients with an index diagnosis of GIM was accurately identified. There was wide variability in clinical practice patterns including biopsy practice, HP treatment and eradication confirmation testing, and surveillance recommendations. This work demonstrates that there is a major unmet need for quality improvement efforts to standardize care for patients with GIM, a premalignant condition, and inform future prospective studies in a US population., (© The Author(s), 2022.)