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The indolizidine core of virosinine A was synthesized by means of a microwave-promoted cascade reaction featuring 5- exo - trig iminyl radical cyclization, thiyl radical elimination, and intramolecular imine alkylation. The resulting bicyclic iminium ion underwent stereoselective reduction by Red-Al to deliver the target compound. DFT calculations suggested that both the radical cyclization and thiyl radical elimination steps are reversible at high reaction temperatures.

Intracellular flow cytometry is a powerful technique that can be used to interrogate signalling in rare cellular populations. The strengths of the technique are that massively parallel readouts can be gained from thousands of single cells simultaneously, and the assay is fast and relatively straightforward. This plate-based protocol enables different doses and different timepoints of stimulation to be assessed and has been optimized for rare B cell populations. Combining this technique with high-dimensional flow cytometry enables multiple signalling proteins to be measured with high confidence., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Multisensory perception is critical for effective interaction with the environment, but human responses to multisensory stimuli vary across the lifespan and appear changed in some atypical populations. In this review chapter, we consider multisensory integration within a normative Bayesian framework. We begin by outlining the complex computational challenges of multisensory causal inference and reliability-weighted cue integration, and discuss whether healthy young adults behave in accordance with normative Bayesian models. We then compare their behaviour with various other human populations (children, older adults, and those with neurological or neuropsychiatric disorders). In particular, we consider whether the differences seen in these groups are due only to changes in their computational parameters (such as sensory noise or perceptual priors), or whether the fundamental computational principles (such as reliability weighting) underlying multisensory perception may also be altered. We conclude by arguing that future research should aim explicitly to differentiate between these possibilities., (© 2024. The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.)

The workforce of mental health providers serving lesbian, gay, bisexual, transgender, queer, and/or questioning (LGBTQ+) youth lags far behind the demand for LGBTQ-focused mental health care. Unsatisfactory training and a lack of standardized training metrics for accredited programs perpetuate the lack of preparedness among providers. The presence of LGBTQ+ faculty and mentors in medical education increases the amount of LGBTQ+ content taught to trainees and improves professional development for LGBTQ+ trainees. Inclusive workplace practices and affirming care policies may also improve retention and recruitment of LGBTQ-serving mental health providers., Competing Interests: Disclosure The authors have no relevant financial disclosures nor conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To compare mortality of dogs undergoing partial staphylectomy using conventional incisional, carbon dioxide (CO 2 ) laser, and bipolar vessel sealing device (BVSD) techniques for the treatment of brachycephalic obstructive airway syndrome (BOAS)., Study Design: Retrospective multicenter cohort study., Animals: A total of 606 client-owned English bulldogs, French bulldogs, and pugs., Methods: Medical records from 2011 to 2021 were reviewed for signalment, history, surgical technique, length of hospitalization, and complications. Multivariate statistical analysis was performed to compare odds of mortality between the three techniques of staphylectomy., Results: The overall mortality rate was 24/606 (4.0%). Of those 24 dogs, staphylectomy was performed with BVSD technique in 13 cases, with CO 2 laser in nine, and using conventional incisional technique in two. Nine dogs were graded II or III laryngeal collapse, 14 were graded I, and one was unknown. BVSD technique was associated with mortality prior to discharge compared to the other two techniques (OR = 6.0, 95% CI: 1.3-28.4, p = .023). No differences were detected between conventional incisional and CO 2 laser techniques. Concurrent higher grade (stage II or III) laryngeal collapse was independently associated with mortality prior to discharge (OR = 4.6, 95% CI: 1.8-11.8, p = .002)., Conclusion: The use of BVSD and grade of laryngeal collapse were associated with a higher risk of perioperative mortality., Clinical Significance: Clinical studies using a randomized trial design should be conducted to further determine the putative influence of surgical instrumentation in the perioperative mortality rate following multilevel surgery in dogs with BOAS., (© 2023 American College of Veterinary Surgeons.)

Recalcitrant nail plate infections can be life-long problems because localizing antifungal agents into infected tissues is problematic. In this systematic review, guided by the SPIDER method, we extracted chemical nail permeation data for 38 compounds from 16 articles, and analyzed the data using quantitative structure-property relationships (QSPRs). Our analysis demonstrated that low-molecular weight was essential for effective nail penetration, with <120 g/mol being preferred. Interestingly, chemical polarity had little effect on nail penetration; therefore, small polar molecules, which effectively penetrate the nail, but not the skin, should be set as the most desirable target chemical property in new post-screen onychomycosis candidate selections., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: Menu labeling has been implemented in restaurants in some US jurisdictions as early as 2008, but the extent to which menu labeling is associated with calories purchased is unclear., Objective: To estimate the association of menu labeling with calories and nutrients purchased and assess geographic variation in results., Design, Setting, and Participants: A cohort study was conducted with a quasi-experimental design using actual transaction data from Taco Bell restaurants from calendar years 2007 to 2014 US restaurants with menu labeling matched to comparison restaurants using synthetic control methods. Data were analyzed from May to October 2023., Exposure: Menu labeling policies in 6 US jurisdictions., Main Outcomes and Measures: The primary outcome was calories per transaction. Secondary outcomes included total and saturated fat, carbohydrates, protein, sugar, fiber, and sodium., Results: The final sample included 2329 restaurants, with menu labeling in 474 (31 468 restaurant-month observations). Most restaurants (94.3%) were located in California. Difference-in-differences model results indicated that customers purchased 24.7 (95% CI, 23.6-25.7) fewer calories per transaction from restaurants in the menu labeling group in the 3- to 24-month follow-up period vs the comparison group, including 21.9 (95% CI, 20.9-22.9) fewer calories in the 3- to 12-month follow-up period and 25.0 (95% CI, 24.0-26.1) fewer calories in the 13- to 24-month follow-up period. Changes in the nutrient content of transactions were consistent with calorie estimates. Findings in California were similar to overall estimates in magnitude and direction; yet, among restaurants outside of California, no association was observed in the 3- to 24-month period. The outcome of menu labeling also differed by item category and time of day, with a larger decrease in the number of tacos vs other items purchased and a larger decrease in calories purchased during breakfast vs other times of the day in the 3- to 24-month period., Conclusions and Relevance: In this quasi-experimental cohort study, fewer calories were purchased in restaurants with calorie labels compared with those with no labels, suggesting that consumers are sensitive to calorie information on menu boards, although associations differed by location.

Heterozygous GRN (progranulin) mutations cause frontotemporal dementia (FTD) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein levels are limited. Here, we tested the efficacy of ASOs as enhancers of progranulin expression by sterically blocking the miR-29b binding site in the 3' UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin protein in iPSC-derived neurons and in a humanized GRN mouse model. In FRET-based assays, the ASOs effectively competed for miR-29b from binding to the GRN 3' UTR RNA. The ASOs increased levels of newly synthesized progranulin protein by increasing its translation, as revealed by polysome profiling. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency., Competing Interests: Conflict of interest K. L., P. J.-N., and F. R. are paid employees of Ionis Pharmaceuticals. Ionis Pharmaceuticals and Saint Louis University have filed for patents based on using GRN ASOs to treat frontotemporal dementia. The authors declare that they have no other conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

A novel subtractive manufacturing method to produce bespoke tablets with immediate and extended drug release is presented. This is the first report on applying fusion laser cutting to produce bespoke furosemide solid dosage forms based on pharmaceutical-grade polymeric carriers. Cylindric tablets of different sizes were produced by controlling the two-dimensional design of circles of the corresponding diameter. Immediate and extended drug release patterns were achieved by modifying the composition of the polymeric matrix. Thermal analysis and XRD indicated that furosemide was present in an amorphous form. The laser-cut tablets demonstrated no significant drug degradation (<2%) nor the formation of impurities were identified. Multi-linear regression was used to quantify the influences of laser-cutting process parameters (laser energy levels, scan speeds, and the number of laser applications) on the depth of the laser cut. The utility of this approach was exemplified by manufacturing tablets of accurate doses of furosemide. Unlike additive or formative manufacturing, the reported approach of subtractive manufacturing avoids the modification of the structure, e.g., the physical form of the drug or matrix density of the tablet during the production process. Hence, fusion laser cutting is less likely to modify critical quality attributes such as release patterns or drug contents. In a point-of-care manufacturing scenario, laser cutting offers a significant advantage of simplifying quality control and a real-time release of laser-cut products such as solid dosage forms and implants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Mucopolysaccharidosis (MPS) II is a rare, X-linked lysosomal storage disease. Approximately two-thirds of patients have central nervous system involvement with some demonstrating progressive cognitive impairment (neuronopathic disease). The natural history of cognitive and adaptive function in patients with MPS II is not well-defined. This 2-year, prospective, observational study evaluated the neurodevelopmental trajectories of boys with MPS II aged ≥ 2 years and < 18 years., Results: Overall, 55 patients were enrolled. At baseline, mean (standard deviation [SD]) age was 5.60 (3.32) years; all patients were receiving intravenous idursulfase. Cognitive and adaptive function were assessed using the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) scores, respectively. Baseline mean (SD) DAS-II GCA and VABS-II ABC scores were 78.4 (19.11) and 83.7 (14.22), respectively, indicating low cognitive function and moderately low adaptive behavior. Over 24 months, modest deteriorations in mean (SD) scores were observed for DAS-II GCA (-3.8 [12.7]) and VABS-II ABC (-2.0 [8.07]). Changes in DAS-II GCA scores varied considerably, and data suggested the existence of four potential patient subgroups: (1) patients with marked early impairment and rapid subsequent decline, (2) patients with marked early impairment then stabilization, (3) patients with mild early impairment then stabilization, and (4) patients without impairment who remained stable. Subgroup analyses revealed numerically greater DAS-II GCA score reductions from baseline in patients aged < 7 years at baseline (vs. those aged ≥ 7 years) and in patients with DAS-II GCA scores ≤ 70 at baseline (vs. those with scores > 70); between-group differences were nonsignificant. No clear subgroups or patterns were identified for individual changes in VABS-II ABC scores. In total, 49 patients (89.1%) reported ≥ 1 adverse event (AE) and nine patients (16.4%) reported serious AEs., Conclusions: Some patients with MPS II had rapid declines in cognitive ability, whereas others remained relatively stable after an initial decline. These insights provide a basis for more detailed analyses of different patient subgroups, which may enhance the definition and understanding of factors that influence cognitive and adaptive function in MPS II., Trial Registration: ClinicalTrials.gov, NCT01822184. Registered retrospectively: April 2, 2013., (© 2023. The Author(s).)

Background: Overprescribing of antibiotics for acute respiratory infections (ARIs) remains a major issue in outpatient settings. Use of clinical prediction rules (CPRs) can reduce inappropriate antibiotic prescribing but they remain underutilized by physicians and advanced practice providers. A registered nurse (RN)-led model of an electronic health record-integrated CPR (iCPR) for low-acuity ARIs may be an effective alternative to address the barriers to a physician-driven model., Methods: Following qualitative usability testing, we will conduct a stepped-wedge practice-level cluster randomized controlled trial (RCT) examining the effect of iCPR-guided RN care for low acuity patients with ARI. The primary hypothesis to be tested is: Implementation of RN-led iCPR tools will reduce antibiotic prescribing across diverse primary care settings. Specifically, this study aims to: (1) determine the impact of iCPRs on rapid strep test and chest x-ray ordering and antibiotic prescribing rates when used by RNs; (2) examine resource use patterns and cost-effectiveness of RN visits across diverse clinical settings; (3) determine the impact of iCPR-guided care on patient satisfaction; and (4) ascertain the effect of the intervention on RN and physician burnout., Discussion: This study represents an innovative approach to using an iCPR model led by RNs and specifically designed to address inappropriate antibiotic prescribing. This study has the potential to provide guidance on the effectiveness of delegating care of low-acuity patients with ARIs to RNs to increase use of iCPRs and reduce antibiotic overprescribing for ARIs in outpatient settings., Trial Registration: ClinicalTrials.gov Identifier: NCT04255303, Registered February 5 2020, https://clinicaltrials.gov/ct2/show/NCT04255303 ., (© 2023. The Author(s).)

Disadvantages of systemically administered immunomodulatory anti-tumor therapies include poor efficacy and high toxicity. Direct intratumoral injection of a drug is often associated with rapid efflux from the site of administration, thus reducing local exposure and therapeutic efficacy, while potentially increasing systemic adverse events. To address this, a sustained release prodrug technology was developed using a transient conjugation (TransCon TM ) technology to provide long-term high local drug exposure after injection in the tumor while minimizing systemic exposure. TransCon technology for systemic delivery is clinically validated, with multiple compounds in late-stage clinical development and approval of a once-weekly growth hormone for pediatric growth hormone deficiency. As a further application of this technology, this report describes the design, preparation, and functional characterization of hydrogel microspheres as insoluble, yet degradable carrier system. Microspheres were obtained after reaction of PEG-based polyamine dendrimers and bifunctional crosslinkers. Resiquimod, a TLR7/8 agonist, and axitinib, a vascular endothelial growth factor tyrosine kinase inhibitor, were chosen as anti-cancer drugs. The drugs were covalently attached to the carrier by linkers, which released the drugs under physiological conditions. Essentially all resiquimod or axitinib was released over weeks before physical degradation of the hydrogel microsphere was observed. In summary, TransCon Hydrogel technology allows localized sustained-release drug delivery for cancer therapy enabling high local drug concentrations while at the same time ensuring low systemic drug exposure over weeks with a single injection, which may improve the therapeutic index and improve efficacy, while minimizing systemic adverse events. A hydrogel prodrug of resiquimod, TransCon TLR7/8 agonist, is currently being investigated in clinical trials of patients with solid tumors (NCT04799054)., Competing Interests: Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kennett Sprogoe reports a relationship with Ascendis Pharma that includes: employment. Torben Lessmann reports a relationship with Ascendis Pharma that includes: employment. Seth A. Jones reports a relationship with Ascendis Pharma that includes: employment. Tobias Voigt reports a relationship with Ascendis Pharma that includes: employment. Samuel Weisbrod reports a relationship with Ascendis Pharma that includes: employment. Oliver Kracker reports a relationship with Ascendis Pharma that includes: employment. Steffen Winter reports a relationship with Ascendis Pharma that includes: employment. Luis Alejandro Zuniga reports a relationship with Ascendis Pharma that includes: employment. Sebastian Stark reports a relationship with Ascendis Pharma that includes: employment. Nicola Bisek reports a relationship with Ascendis Pharma that includes: employment. Kennett Sprogoe has patent pending to Ascendis Pharma A/S. Torben Lessmann has patent pending to Ascendis Pharma A/S. Samuel Weisbrod has patent pending to Ascendis Pharma A/S. Nicola Bisek has patent pending to Ascendis Pharma A/S. Sebastian Stark has patent pending to Ascendis Pharma A/S. Tobias Voigt has patent pending to Ascendis Pharma A/S., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Subcortical brain morphometry matures across adolescence and young adulthood, a time when many youth engage in escalating levels of alcohol use. Initial cross-sectional studies have shown alcohol use is associated with altered subcortical morphometry. However, longitudinal evidence of sex-specific neuromaturation and associations with alcohol use remains limited. This project used generalized additive mixed models to examine sex-specific development of subcortical volumes and associations with recent alcohol use, using 7 longitudinal waves (n = 804, 51% female, ages 12-21 at baseline) from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA). A second, independent, longitudinal dataset, with up to four waves of data (n = 467, 43% female, ages 10-18 at baseline), was used to assess replicability. Significant, replicable non-linear normative volumetric changes with age were evident in the caudate, putamen, thalamus, pallidum, amygdala and hippocampus. Significant, replicable negative associations between subcortical volume and alcohol use were found in the hippocampus in all youth, and the caudate and thalamus in female but not male youth, with significant interactions present in the caudate, thalamus and putamen. Findings suggest a structural vulnerability to alcohol use, or a predisposition to drink alcohol based on brain structure, with female youth potentially showing heightened risk, compared to male youth., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Language concordance between health care practitioners and patients have recently been shown to lower the risk of adverse health events. Continuity of care also been shown to have the same impact., Objective: The purpose of this paper is to examine the relative effectiveness of both continuity of care and language concordance as alternative or complementary interventions to improve health outcomes of people with limited English proficiency., Design: A multivariable logistic regression model using rehospitalization as the dependent variable was built. The variable of interest was created to compare language concordance and continuity of care., Participants: The final sample included 22,103 patients from the New York City area between 2010 and 2015 who were non-English-speaking and admitted to their home health site following hospital discharge., Measures: The odds ratio (OR) average marginal effect (AME) of each included variable was calculated for model analysis., Results: When compared with low continuity of care and high language concordance, high continuity of care and high language concordance significantly decreased readmissions (OR=0.71, 95% CI: 0.62-0.80, P<0.001, AME=-4.95%), along with high continuity of care and low language concordance (OR=0.80, 95% CI: 0.74-0.86, P<0.001, AME=-3.26%). Low continuity of care and high language concordance did not significantly impact readmissions (OR=1.04, 95% CI: 0.86-1.26, P=0.672, AME=0.64%)., Conclusion: In the US home health system, enhancing continuity of care for those with language barriers may be helpful to address disparities and reduce hospital readmission rates., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Einstein's general theory of relativity from 1915 1 remains the most successful description of gravitation. From the 1919 solar eclipse 2 to the observation of gravitational waves 3 , the theory has passed many crucial experimental tests. However, the evolving concepts of dark matter and dark energy illustrate that there is much to be learned about the gravitating content of the universe. Singularities in the general theory of relativity and the lack of a quantum theory of gravity suggest that our picture is incomplete. It is thus prudent to explore gravity in exotic physical systems. Antimatter was unknown to Einstein in 1915. Dirac's theory 4 appeared in 1928; the positron was observed 5 in 1932. There has since been much speculation about gravity and antimatter. The theoretical consensus is that any laboratory mass must be attracted 6 by the Earth, although some authors have considered the cosmological consequences if antimatter should be repelled by matter 7-10 . In the general theory of relativity, the weak equivalence principle (WEP) requires that all masses react identically to gravity, independent of their internal structure. Here we show that antihydrogen atoms, released from magnetic confinement in the ALPHA-g apparatus, behave in a way consistent with gravitational attraction to the Earth. Repulsive 'antigravity' is ruled out in this case. This experiment paves the way for precision studies of the magnitude of the gravitational acceleration between anti-atoms and the Earth to test the WEP., (© 2023. The Author(s).)

Objective: To elicit Head Start (HS) families' and employees' perspectives on family experiences with food and nutrition insecurity (FNI) and identify how HS addresses them., Methods: Four moderated virtual focus groups with 27 HS employee and family participants occurred from August 2021 to January 2022. Qualitative analysis used an iterative inductive/deductive approach., Results: Findings were summarized in a conceptual framework and suggested that HS's current 2-generational approach is useful for families when addressing multilevel factors affecting FNI. The role of the family advocate is essential. In addition to increasing access to nutritious foods, emphasis should also be placed on skills and education to decrease generational unhealthy behaviors., Conclusions and Implications: Head Start intervenes in generational cycles of FNI by using the family advocate to add to skills building for 2-generational health. Other programs targeting underserved children can use a similar structure for the greatest impact on FNI., (Copyright © 2023 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.)

Distress tolerance, the ability to persist while experiencing negative psychological states, is essential for regulating emotions and is a transdiagnostic risk/resiliency trait for multiple psychopathologies. Studying distress tolerance during adolescence, a period when emotion regulation is still developing, may help identify early risk and/or protective factors. This study included 40 participants (mean scan age = 17.5 years) and using an emotional Go-NoGo functional magnetic resonance imaging task and voxel-wise regression analysis, examined the association between brain response during emotional face processing and future distress tolerance (two ± 0.5 years), controlling for sex assigned at birth, age, and time between visits. Post-hoc analyses tested the mediating role of distress tolerance on the emotional reactivity and depressive symptom relationship. Whole-brain analysis showed greater inferior occipital gyrus activation was associated with less distress tolerance at follow-up. The mediating role of distress tolerance demonstrated a trend-level indirect effect. Findings suggest that individuals who allocate greater visual resources to emotionally salient information tend to exhibit greater challenges in tolerating distress. Distress tolerance may help to link emotional reactivity neurobiology to future depressive symptoms. Building distress tolerance through emotion regulation strategies may be an appropriate strategy for decreasing depressive symptoms., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Microwave irradiation of O -phenyloximes triggers N-O homolysis and 1,5-hydrogen atom transfer (HAT), resulting in formal γ-C-H functionalization of ketones after trapping of the radical intermediate and in situ imine hydrolysis. The Lewis acid InCl 3 ·H 2 O facilitated HAT, enabling functionalization of benzylic and nonbenzylic secondary carbon atoms. Functionalization of primary carbons was feasible but afforded low yields, requiring ClCH 2 CO 2 H instead of InCl 3 ·H 2 O as an additive. C-O and C-C bond formation could both be accomplished by this method.

Cytokines that signal via STAT1 and STAT3 transcription factors instruct decisions affecting tissue homeostasis, antimicrobial host defense, and inflammation-induced tissue injury. To understand the coordination of these activities, we applied RNA sequencing, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing to identify the transcriptional output of STAT1 and STAT3 in peritoneal tissues from mice during acute resolving inflammation and inflammation primed to drive fibrosis. Bioinformatics focused on the transcriptional signature of the immunomodulatory cytokine IL-6 in both settings and examined how profibrotic IFN-γ-secreting CD4+ T cells altered the interpretation of STAT1 and STAT3 cytokine cues. In resolving inflammation, STAT1 and STAT3 cooperated to drive stromal gene expression affecting antimicrobial immunity and tissue homeostasis. The introduction of IFN-γ-secreting CD4+ T cells altered this transcriptional program and channeled STAT1 and STAT3 to a previously latent IFN-γ activation site motif in Alu-like elements. STAT1 and STAT3 binding to this conserved sequence revealed evidence of reciprocal cross-regulation and gene signatures relevant to pathophysiology. Thus, we propose that effector T cells retune the transcriptional output of IL-6 by shaping a regulatory interplay between STAT1 and STAT3 in inflammation., (Copyright © 2023 The Authors.)

Inhibitory CD4 + T cells have been linked with suboptimal immune responses against cancer and pathogen chronicity. However, the mechanisms that underpin the development of these regulatory cells, especially in the context of ongoing antigen exposure, have remained obscure. To address this knowledge gap, we undertook a comprehensive functional, phenotypic, and transcriptomic analysis of interleukin (IL)-10-producing CD4 + T cells induced by chronic infection with murine cytomegalovirus (MCMV). We identified these cells as clonally expanded and highly differentiated T H 1-like cells that developed in a T-bet-dependent manner and coexpressed arginase-1 (Arg1), which promotes the catalytic breakdown of L-arginine. Mice lacking Arg1-expressing CD4 + T cells exhibited more robust antiviral immunity and were better able to control MCMV. Conditional deletion of T-bet in the CD4 + lineage suppressed the development of these inhibitory cells and also enhanced immune control of MCMV. Collectively, these data elucidated the ontogeny of IL-10-producing CD4 + T cells and revealed a previously unappreciated mechanism of immune regulation, whereby viral persistence was facilitated by the site-specific delivery of Arg1., Competing Interests: MC, KL, KM, MM, LC, AC, JS, RA, SC, VK, KL, OB, DW, SJ, DC, DP, IH No competing interests declared, (© 2023, Clement et al.)

Background: Mucopolysaccharidosis IIIC (MPSIIIC) is one of four Sanfilippo diseases sharing clinical symptoms of severe cognitive decline and shortened lifespan. The missing enzyme, heparan sulfate acetyl-CoA: α-glucosaminide-N-acetyltransferase (HGSNAT), is bound to the lysosomal membrane, therefore cannot cross the blood-brain barrier or diffuse between cells. We previously demonstrated disease correction in MPSIIIC mice using an Adeno-Associated Vector (AAV) delivering HGSNAT via intraparenchymal brain injections using an AAV2 derived AAV-truetype (AAV-TT) serotype with improved distribution over AAV9., Methods: Here, intraparenchymal AAV was delivered in sheep using catheters or Hamilton syringes, placed using Brainlab cranial navigation for convection enhanced delivery, to reduce proximal vector expression and improve spread., Results: Hamilton syringes gave improved AAV-GFP distribution, despite lower vector doses and titres. AAV-TT-GFP displayed moderately better transduction compared to AAV9-GFP but both serotypes almost exclusively transduced neurons. Functional HGSNAT enzyme was detected in 24-37% of a 140g gyrencephalic sheep brain using AAV9-HGSNAT with three injections in one hemisphere., Conclusions: Despite variabilities in volume and titre, catheter design may be critical for efficient brain delivery. These data help inform a clinical trial for MPSIIIC., (© 2023. The Author(s).)

Mitochondrial uncoupling protein 1 (UCP1) gives brown adipose tissue of mammals its specialized ability to burn calories as heat for thermoregulation. When activated by fatty acids, UCP1 catalyzes the leak of protons across the mitochondrial inner membrane, short-circuiting the mitochondrion to generate heat, bypassing ATP synthesis. In contrast, purine nucleotides bind and inhibit UCP1, regulating proton leak by a molecular mechanism that is unclear. We present the cryo-electron microscopy structure of the GTP-inhibited state of UCP1, which is consistent with its nonconducting state. The purine nucleotide cross-links the transmembrane helices of UCP1 with an extensive interaction network. Our results provide a structural basis for understanding the specificity and pH dependency of the regulatory mechanism. UCP1 has retained all of the key functional and structural features required for a mitochondrial carrier-like transport mechanism. The analysis shows that inhibitor binding prevents the conformational changes that UCP1 uses to facilitate proton leak.

Enzyme replacement therapy shows remarkable clinical improvement in treating lysosomal storage disorders. However, this therapeutic approach is hampered by limitations in the delivery of the enzyme to cells and tissues. Therefore, there is an urgent, unmet clinical need to develop new strategies to enhance the enzyme delivery to diseased cells. Graphene-based materials, due to their dimensionality and favourable pattern of interaction with cells, represent a promising platform for the loading and delivery of therapeutic cargo. Herein, the potential use of graphene-based materials, including defect-free graphene with positive or negative surface charge and graphene oxide with different lateral dimensions, was investigated for the delivery of lysosomal enzymes in fibroblasts derived from patients with Mucopolysaccharidosis VI and Pompe disease. We report excellent biocompatibility of all graphene-based materials up to a concentration of 100 μg mL -1 in the cell lines studied. In addition, a noticeable difference in the uptake profile of the materials was observed. Neither type of graphene oxide was taken up by the cells to a significant extent. In contrast, the two types of graphene were efficiently taken up, localizing in the lysosomes. Furthermore, we demonstrate that cationic graphene flakes can be used as carriers for arylsulfatase B enzyme, for the delivery of the lacking enzyme to the lysosomes of Mucopolysaccharidosis VI fibroblasts. Arylsulfatase B complexed with cationic graphene flakes not only retained the enzymatic activity, but also exerted biological effects almost twice as high as arylsulfatase B alone in the clearance of the substrate in Mucopolysaccharidosis VI fibroblasts. This study lays the groundwork for the potential use of graphene-based materials as carriers for enzyme replacement therapy in lysosomal storage disorders.

Objectives: Physical examination and computed tomography (CT) are useful to rule out cervical spine injury (CSI). Computed tomography scans increase lifetime cancer risk in children from radiation exposure. Most CSI in children occur between the occiput and C4. We developed a cervical spine (C-spine) clearance guideline to reduce unnecessary CTs and radiation exposure in pediatric trauma patients., Methods: A pediatric C-spine clearance guideline was implemented in September 2018 at our Level 2 Pediatric Trauma Center. Guidance included CT of C1 to C4 to scan only high-yield regions versus the entire C-spine and decrease radiation dose. A retrospective cohort study was conducted comparing preguideline and postguideline of all pediatric trauma patients younger than 8 years screened for CSI from July 2017 to December 2020. Primary endpoints included the following: number of full C-spine and C1 to C4 CT scans and radiation dose. Secondary endpoints were CSI rate and missed CSI. Results were compared using χ 2 and Wilcoxon rank-sum test with P < 0.05 significant., Results: The review identified 726 patients: 273 preguideline and 453 postguideline. A similar rate of total C-spine CTs were done in both groups (23.1% vs 23.4%, P = 0.92). Full C-spine CTs were more common preguideline (22.7% vs 11.9%, P < 0.001), whereas C1 to C4 CT scans were more common post-guideline (11.5% vs 0.4%, P < 0.001). Magnetic resonance imaging utilization and CSIs identified were similar in both groups. The average radiation dose was lower postguideline (114 vs 265 mGy·cm -1 ; P < 0.001). There were no missed CSI., Conclusions: A pediatric C-spine clearance guideline led to increasing CT of C1 to C4 over full C-spine imaging, reducing the radiation dose in children., Level of Evidence: Level IV, therapeutic., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Attention-deficit/hyperactivity disorder (ADHD) is a complex behavioral disorder, often difficult and time consuming to diagnose. Laboratory assessment of ADHD-related constructs of attention and motor activity may be helpful in elucidating neurobiology; however, neuroimaging studies evaluating laboratory measures of ADHD are lacking. In this preliminary study, we assessed the association between fractional anisotropy (FA), a measure of white matter microstructure, and laboratory measures of attention and motor behavior using the QbTest, a widely used measure thought to improve clinician diagnostic confidence. This is the first look at neural correlates of this widely used measure. The sample included adolescents and young adults (ages 12-20, 35% female) with ADHD (n = 31) and without (n = 52). As expected, ADHD status was associated with motor activity, and cognitive inattention and impulsivity in the laboratory. With regard to MRI findings, laboratory observed motor activity and inattention were associated with greater FA in white matter regions of the primary motor cortex. All three laboratory observations were associated with lower FA in regions subserving fronto-striatal-thalamic and frontoparietal (i.e. superior longitudinal fasciculus) circuitry. Further, FA in white matter regions of the prefrontal cortex appeared to mediate the relationship between ADHD status and motor activity on the QbTest. These findings, while preliminary, suggest that performance on certain laboratory tasks is informative with regard to neurobiological correlates of subdomains of the complex ADHD phenotype. In particular, we provide novel evidence for a relationship between an objective measure of motor hyperactivity and white matter microstructure in motor and attentional networks., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest financial or otherwise., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Studies in animals and humans suggest that greater levels of sensation seeking and alcohol use are related to individual differences in drug-induced dopamine release. However, it remains unclear whether drug-induced alterations in the functional synchrony between mesostriatal regions are related to sensation seeking and alcohol use., Methods: In this within-subject masked-design study, 21-year-old participants (n = 34) underwent functional magnetic resonance imaging to measure ventral tegmental area (VTA) resting-state functional connectivity to the striatum after receiving alcohol (target blood alcohol concentration 0.08 g/dL) or placebo. Participants also completed the UPPS-P Impulsive Behavior Scale to assess sensation seeking, the Young Adult Alcohol Consequences Questionnaire, and self-reported patterns of alcohol and drug use., Results: Voxel-wise analyses within the striatum demonstrated that during the alcohol condition (compared with placebo) young adults had less connectivity between the VTA and bilateral caudate (p < 0.05 corrected). However, young adults exhibiting smaller alcohol-induced decreases or increases in VTA-left caudate connectivity reported greater sensation seeking., Conclusion: These findings provide novel information about how acute alcohol impacts resting-state connectivity, an effect that may be driven by the complex pre and postsynaptic effects of alcohol on various neurotransmitters including dopamine. Further, alcohol-induced differences in VTA connectivity represent a plausible mechanistic substrate underlying sensation seeking., (© 2023 Research Society on Alcohol.)

Plant communities in North American prairie pothole wetlands vary depending on hydrology, salinity, and anthropogenic disturbance in and around the wetland. We assessed prairie pothole conditions on United States Fish and Wildlife Service fee-title lands in North Dakota and South Dakota to improve our understanding of current conditions and plant community composition. Species-level data were collected at 200 randomly chosen temporary and seasonal wetland sites located on native prairie remnants ( n = 48) and previously cultivated lands that were reseeded into perennial grassland ( n = 152). The majority of species surveyed appeared infrequently and were low in relative cover. The four most frequently observed species were introduced invasive species common to the Prairie Pothole Region of North America. Our results suggested relative cover of a few invasive species (i.e., Bromus inermis Leyss., Phalaris arundinacea L., and Typha ×glauca Godr. (pro sp.) [angustifolia or domingensis × latifolia]) affect patterns of plant community composition. Wetlands in native and reseeded grasslands possessed distinct plant community composition related to invasive species' relative cover. Invasive species continue to be prevalent throughout the region and pose a major threat to biological diversity, even in protected native prairie remnants. Despite efforts to convert past agricultural land into biologically diverse, productive ecosystems, invasive species continue to dominate these landscapes and are becoming prominent in prairie potholes located in native areas.

Background: Brain Injury Guidelines (BIG) were developed to stratify traumatic brain injuries (TBIs) by severity to decrease unnecessary CT imaging and neurosurgical consultation in low-risk cases. This study evaluated the potential effect of a modified pediatric BIG (pBIG) algorithm would have on resource utilization., Methods: Isolated TBIs (<18 years) were queried from our Pediatric Trauma Registry from 2017 to 2020. Injuries were classified as mild (pBIG 1), moderate (pBIG 2), or severe (pBIG 3) based on neurologic status, skull fractures, size, and the number of bleeds. Modifications from the institutional adult algorithm were upgrading <4 mm epidural hematomas to pBIG 2 and eliminating interfacility transfer as a pBIG 2 criteria. The proposed pBIG 1 and 2 care plans do not include routine repeat CTs or neurosurgical consultation., Results: A total of 314 children with a mean age of 4.9 years were included. Skull fractures (213, 68%) and subdural hematomas (162, 52%) were the most common injuries. 89 (28%) children had repeat head CTs (2 (7%) pBIG 1, 26 (25%) pBIG 2, 61 (34%) pBIG 3). Neurosurgical consultation was obtained in 306 (98%), with 50 (16%) requiring intervention (1 (1%) pBIG 2 and 49 (27%) pBIG 3). Following the proposed pBIG would decrease neurosurgical consults to 181 (58%) and repeat CTs to 63 (20%). Following the algorithm, 91 (29%) kids would have been admitted to a higher level of care and 45 (14.3%) to a lower level., Conclusions: Implementation of our pBIG algorithm would decrease neurosurgery consults (40% reduction) and repeat head CTs (29% reduction)., Competing Interests: Conflict of Interest There are no conflicts of interest with this work., (Copyright © 2022. Published by Elsevier Inc.)

Objective: Substance misuse is often associated with emotional dysregulation. Understanding the neurobiology of emotional responsivity and regulation as it relates to substance use in adolescence may be beneficial for preventing future use., Method: The present study used a community sample, ages 11-21 years old ( N = 130, M age = 17), to investigate the effects of alcohol and marijuana use on emotional reactivity and regulation using an Emotional Go-NoGo task during functional magnetic resonance imaging. The task consisted of three conditions, where target (Go) stimuli were either happy, scared, or calm faces. Self-report lifetime (and past-90-day) drinking and marijuana use days were provided at all visits., Results: Substance use was not differentially related to task performance based on condition. Whole-brain linear mixed-effects analyses (controlling for age and sex) found that more lifetime drinking occasions was associated with greater neural emotional processing (Go trials) in the right middle cingulate cortex during scared versus calm conditions. In addition, more marijuana use occasions were associated with less neural emotional processing during scared versus calm conditions in the right middle cingulate cortex and right middle and inferior frontal gyri. Substance use was not associated with brain activation during inhibition (NoGo trials)., Conclusions: These findings demonstrate that substance use-related alterations in brain circuitry are important for attention allocation and the integration of emotional processing and motor response when viewing negative emotional stimuli.

Introduction: Telehealth is the use of electronic information and technology for long-distance clinical care. In direct-to-patient (DTP) telehealth, the patient initiates care from a personal computer or mobile device to a medical provider. While information on standard clinic-to-clinic telehealth exists, less is known about DTP telehealth in pediatric populations. Using quantitative and qualitative data, we examined DTP telehealth for low-income pediatric patient-families and compared the experience of English and non-English speakers., Method: Telehealth visits for acute and preventive care took place from April 2020 to May 2020 at a pediatric primary care clinic (80% Medicaid-insured, 40% non-English-speaking). Patients and primary care providers conducted the visit through the clinic's portal or other platforms (WhatsApp, FaceTime, Zoom). Providers completed an electronic survey with patient feedback about the telehealth experience and their own observations. An iterative inductive/deductive approach informed a coding scheme for free-text survey responses consisting of five domains., Results: REDCap surveys were completed for 258 (52%) of telehealth visits. There was an overrepresentation of English visits compared to the overall clinic population and the majority of visits were via mobile phone. Visits with English speakers utilized the patient portal and had positive process ease ratings more often than those with non-English speakers. Providers rated most telehealth visits as satisfactory, with contributing elements including family call environment, technology process and experience, value added, and barriers., Discussion: Expanding telehealth in pediatrics without worsening health disparities requires building digital health that is user-friendly on mobile technology, facilitating patient preferred language, and simplifying logistical processes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The commentary provided by Maase et al. [...].

Objective: To leverage large scale genetic association data to investigate the interplay between circulating cytokines and cardiometabolic traits, and thus identifying potential therapeutic targets., Design: Bi-directional Mendelian randomisation study., Setting: Genome-wide association studies from three Finnish cohorts (Northern Finland Birth Cohort 1966, Young Finns Study, or FINRISK study), and genetic association summary statistics pooled from observational studies for expression quantitative trait loci and cardiometabolic traits., Participants: Data for 47 circulating cytokines in 13 365 individuals from genome-wide association studies, summary statistic data for up to 21 735 individuals on circulating cytokines, summary statistic gene expression data across 49 tissues in 838 individuals, and summary statistic data for up to 1 320 016 individuals on cardiometabolic traits., Interventions: Relations between circulating cytokines and cardiovascular, anthropometric, lipid, or glycaemic traits (coronary artery disease, stroke, type 2 diabetes mellitus, body mass index, waist circumference, waist to hip ratio, systolic blood pressure, glycated haemoglobin, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, triglycerides, C reactive protein, glucose, fasting insulin, and lifetime smoking)., Main Outcome Methods: Genetic instrumental variables that are biologically plausible for the circulating cytokines were generated. The effects of cardiometabolic risk factors on concentrations of circulating cytokines, circulating cytokines on other circulating cytokines, and circulating cytokines on cardiometabolic outcomes were investigated., Results: Genetic evidence (mendelian randomisation P<0.0011) suggests that higher body mass index, waist circumference, smoking, higher concentrations of lipids, and systolic blood pressure increase circulating concentrations of several inflammatory cytokines and C reactive protein. Evidence for causal relations (mendelian randomisation P<0.0011) were noted between circulating cytokines, including a key role of vascular endothelial growth factor on influencing the concentrations of 10 other cytokines. Both mendelian randomisation (P<0.05) and colocalisation (posterior probability >0.5) suggested that coronary artery disease risk is increased by higher concentrations of circulating tumour necrosis factor related apoptosis-inducing ligand (TRAIL), interleukin-1 receptor antagonist (IL1RA), and macrophage colony-stimulating factor (MCSF)., Conclusion: This study offers insight into inflammatory mediators of cardiometabolic risk factors, cytokine signalling cascades, and effects of circulating cytokines on different cardiometabolic outcomes., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: DG is employed part-time by Novo Nordisk and has received consultancy fees from Policy Wisdom. VS has received honoraria from Novo Nordisk and Sanofi for consultations and travel support from Novo Nordisk. He also has ongoing research collaboration with Bayer Ltd. GKH reports institutional research support from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Ionis, Kowa, Pfizer, Regeneron, Roche, Sanofi, and The Medicines Company; speaker’s bureau and consulting fees from Amgen, Aegerion, Sanofi, and Regeneron (fees paid to the academic institution); and part-time employment at Novo Nordisk, outside of the submitted work. These declarations are all unrelated to this study., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Naturally occurring body movements and collective neural activity both exhibit complex dynamics, often with scale-free, fractal spatiotemporal structure. Scale-free dynamics of both brain and behavior are important because each is associated with functional benefits to the organism. Despite their similarities, scale-free brain activity and scale-free behavior have been studied separately, without a unified explanation. Here, we show that scale-free dynamics of mouse behavior and neurons in the visual cortex are strongly related. Surprisingly, the scale-free neural activity is limited to specific subsets of neurons, and these scale-free subsets exhibit stochastic winner-take-all competition with other neural subsets. This observation is inconsistent with prevailing theories of scale-free dynamics in neural systems, which stem from the criticality hypothesis. We develop a computational model which incorporates known cell-type-specific circuit structure, explaining our findings with a new type of critical dynamics. Our results establish neural underpinnings of scale-free behavior and clear behavioral relevance of scale-free neural activity., Competing Interests: SJ, JB, VN, WS No competing interests declared, (© 2023, Jones et al.)

Objectives: To develop a simulation model to explore the interplay between mechanical stretch and diffusion of large molecules into the skin under locally applied hypobaric pressure, a novel penetration enhancement method., Methods: Finite element method was used to model the skin mechanical deformation and molecular diffusion processes, with validation against in-vitro transdermal permeation experiments. Simulations and experimental data were used together to investigate the transdermal permeation of large molecules under local hypobaric pressure., Results: Mechanical simulations resulted in skin stretching and thinning (20%-26% hair follicle diameter increase, and 21%-27% skin thickness reduction). Concentration of dextrans in the stratum corneum was below detection limit with and without hypobaric pressure. Concentrations in viable epidermis and dermis were not affected by hypobaric pressure (approximately 2 μg [Formula: see text] cm -2 ). Permeation into the receptor fluid was substantially enhanced from below the detection limit at atmospheric pressure to up to 6 μg [Formula: see text] cm -2 under hypobaric pressure. The in-silico simulations compared satisfactorily with the experimental results at atmospheric conditions. Under hypobaric pressure, satisfactory comparison was attained when the diffusion coefficients of dextrans in the skin layers were increased from [Formula: see text] 10 μm 2 [Formula: see text] s -1 to between 200-500 μm 2 [Formula: see text] s -1 ., Conclusions: Application of hypobaric pressure induces skin mechanical stretching and enlarges the hair follicle. This enlargement alone cannot satisfactorily explain the increased transdermal permeation into the receptor fluid under hypobaric pressure. The results from the in-silico simulations suggest that the application of hypobaric pressure increases diffusion in the skin, which leads to improved overall transdermal permeation., (© 2022. The Author(s).)

Antimicrobial host defense is dependent on the rapid recruitment of inflammatory cells to the site of infection, the elimination of invading pathogens, and the efficient resolution of inflammation that minimizes damage to the host. The peritoneal cavity provides an accessible and physiologically relevant system where the delicate balance of these processes may be studied. Here, we describe murine models of peritoneal inflammation that enable studies of competent antimicrobial immunity and inflammation-associated tissue damage as a consequence of recurrent bacterial challenge. The inflammatory hallmarks of these models reflect the clinical and molecular features of peritonitis seen in renal failure patients on peritoneal dialysis. The development of these models relies on the preparation of a cell-free supernatant derived from an isolate of Staphylococcus epidermidis (termed SES). Intraperitoneal administration of SES induces a Toll-like receptor 2-driven acute inflammatory response that is characterized by an initial transient influx of neutrophils that are replaced by a more sustained recruitment of mononuclear cells and lymphocytes. Adaptation of this model using a repeated administration of SES allows investigations into the development of adaptive immunity and the hallmarks associated with tissue remodelling and fibrosis. These models are therefore clinically relevant and provide exciting opportunities to study innate and adaptive immunity and the response of the stromal tissue compartment to bacterial infection and the ensuing inflammatory reaction., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Olipudase alfa is a recombinant human acid sphingomyelinase (ASM) enzyme replacement therapy (ERT) for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). We report 2-year cumulative safety and efficacy data after olipudase alfa treatment in 20 children (four adolescents [12-17 year], nine children [6-11 year], and seven infants/early child [1-5 year]) with baseline splenomegaly and growth deficits who completed the 1-year ASCEND-Peds clinical trial (NCT02292654) and who continue to receive olipudase alfa in a long-term study (NCT02004704). Efficacy endpoints include spleen and liver volumes, diffusing capacity of the lung for carbon monoxide (DL CO ), high-resolution computed tomography (HRCT) lung imaging, lipid profiles, liver function tests, and height Z-scores., Results: All 20 former ASCEND-Peds patients completed at least 2 years of olipudase alfa treatment. No patient discontinued and no new safety issue arose during the second year of treatment; 99% of adverse events were mild or moderate. During year 2, one patient had two treatment-related serious events of hypersensitivity that resolved. Mean reductions from baseline in spleen and liver volumes were 61% and 49%, respectively (p < 0.0001) and mean percent-predicted-DL CO increased by 46.6% (p < 0.0001) in nine patients who performed the test at baseline. Lipid profiles and elevated liver transaminase levels that improved or normalized by 1 year remained stable. Mean height Z-scores improved in all age groups (mean change from baseline 1.17, P < 0.0001)., Conclusion: Olipudase alfa was generally well-tolerated during 2 years of treatment. Improvements in clinically relevant disease endpoints observed during the first year of treatment were maintained or augmented in the second year. Trial registration NCT02004704 registered 26 Nov 2013, https://clinicaltrials.gov/ct2/show/record/NCT02004704 ., (© 2022. The Author(s).)

Introduction: A novel fully porous acetabular titanium shell has been designed to reduce stiffness mismatch between bone and implant and promote osseointegration in complex (cTHA) and revision total hip arthroplasty (rTHA). A highly cross-linked polyethylene (XLPE) liner is cemented within the cup to reduce wear rates and increase survivorship. This study reported the outcomes of an XLPE liner cemented into a novel 3D-printed fully porous cup in cTHA and rTHA., Methods: Presented was a multicenter retrospective review of 40 patients (6 cTHA and 34 rTHA) who underwent THA with a fully porous titanium acetabular cup and cemented XLPE liner. Data were collected on demographics, surgical information, outcomes, including osseointegration and migration and implant survivorship., Results: On average, patients were 71.42 ± 9.97 years old and obese (BMI: 30.36 ± 6.88 kg/m 2 ) and were followed up for a mean time of 2.21 ± 0.77 years. Six patients underwent cTHA and 34 patients underwent rTHA. The mean hospital length of stay was 5.34 ± 3.34 days. Three (7.5%) 90-day readmissions were noted. Harris Hip Scores improved, on average, from 53.87 ± 12.58 preoperatively to 83.53 ± 12.15 postoperatively (P<0.001). One case of acetabular shell aspetic loosening with migration was noted. Thirty-nine of the 40 acetabular components were fully osseointegrated without migration. Two patients underwent re-revision surgery for PJI and one patient received acetabular shell+liner re-revision due to aseptic loosening. Kaplan-Meier analysis showed an all-cause revision-free survival rate of 95.0% at 6 months and 1 year, and 92.0% at 4-years. Aseptic acetabular cup, liner dislocation/loosening, and fracture-free survival was 100% at 6 months and 1-year, and 97.1% at 2 years., Conclusion: The combined use of a novel 3D-printed fully porous titanium acetabular shell and cemented XLPE acetabular liner yielded excellent rates of osseointegration, and all-cause and acetabular aseptic loosening survivorship at a minimum 1-year follow-up. Further long-term studies are needed to assess the longevity of this construct., (© 2022. The Author(s).)

Background: Attention-deficit/hyperactive disorder (ADHD) has substantial heterogeneity in clinical presentation. A potentially important clue may be variation in brain microstructure. Using fractional anisotropy (FA), previous studies have produced equivocal results in relation to ADHD. This may be due to insufficient consideration of possible sex differences and ADHD's multi-componential nature., Methods: Using whole-brain analyses, we investigated the association between FA and both ADHD diagnosis and ADHD symptom domains in a well-characterized, ADHD (n = 234; 32% female youth) and non-ADHD (n = 177; 52% female youth), case-control cohort (ages 7-12). Sex-specific effects were tested., Results: No ADHD group differences were found using categorical assessment of ADHD without consideration of moderators. However, dimensional analyses found total symptoms were associated with higher FA in the superior corona radiata. Further, inattention symptoms were associated with higher FA in the corpus callosum and ansa lenticularis, and lower FA in the superior longitudinal fasciculus, after control for overlap with hyperactivity-impulsivity. Hyperactivity-impulsivity symptoms were associated with higher FA in the superior longitudinal fasciculus, and lower FA in the superior cerebellar peduncles, after control for overlap with inattention. Meanwhile, both categorical and dimensional analyses revealed ADHD-by-sex interactions (voxel-wise p < 0.01). Girls with ADHD had higher FA, but boys with ADHD had lower FA (or no effect), compared to their same-sex peers, in the bilateral anterior corona radiata. Further, higher ADHD symptom severity was associated with higher FA in girls, but lower FA in boys, in the anterior and posterior corona radiata and cerebral peduncles., Conclusions: ADHD symptom domains appear to be differentially related to white matter microstructure, highlighting the multi-componential nature of the disorder. Further, sex differences will be crucial to consider in future studies characterizing ADHD-related differences in white matter microstructure., Competing Interests: Conflicts of interest Joel T. Nigg serves on the JCPP Advances Editorial Advisory Board. The remaining authors have declared that they have no competing or potential conflicts of interest.

SLE is a systemic multi-organ autoimmune condition associated with reduced life expectancy and quality of life. Glucocorticoids (GC) are heavily relied on for SLE treatment but are associated with detrimental metabolic effects. Type 1 interferons (IFN) are central to SLE pathogenesis and may confer GC insensitivity. Glucocorticoid-induced leucine zipper (GILZ) mediates many effects of GC relevant to SLE pathogenesis, but the effect of IFN on GC regulation of GILZ is unknown. We performed in vitro experiments using human PBMC to examine the effect of IFN on GILZ expression. JAK inhibitors tofacitinib and tosylate salt were used in vivo and in vitro respectively to investigate JAK-STAT pathway dependence of our observations. ChiP was performed to examine glucocorticoid receptor (GR) binding at the GILZ locus. Several public data sets were mined for correlating clinical data. High IFN was associated with suppressed GILZ and reduced GILZ relevant to GC exposure in a large SLE population. IFN directly reduced GILZ expression and suppressed the induction of GILZ by GC in vitro in human leukocytes. IFN actions on GILZ expression were dependent on the JAK1/Tyk2 pathway, as evidenced by loss of the inhibitory effect of IFN on GILZ in the presence of JAK inhibitors. Activation of this pathway led to reduced GR binding in key regulatory regions of the GILZ locus. IFN directly suppresses GILZ expression and GILZ upregulation by GC, indicating a potential mechanism for IFN-induced GC resistance. This work has important implications for the ongoing development of targeted GC-sparing therapeutics in SLE., Competing Interests: The 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 Dankers, Northcott, Bennett, D’Cruz, Sherlock, Gearing, Hertzog, Russ, Miceli, Scheer, Fujishiro, Hayakawa, Ikeda, Morand and Jones.)

Sclerotherapy is among the least invasive and most commonly utilised treatment options for varicose veins. Nonetheless, it does not cure varicosities permanently and recurrence rates are of up to 64%. Although sclerosing foams have been extensively characterised with respect to their bench-top properties, such as bubble size distribution and half-life, little is known about their flow behaviour within the venous environment during treatment. Additionally, current methods of foam characterisation do not recapitulate the end-point administration conditions, hindering optimisation of therapeutic efficacy. Here, a therapeutically relevant apparatus has been used to obtain a clinically relevant rheological model of sclerosing foams. This model was then correlated with a therapeutically applicable parameter-i.e., the capability of foams to displace blood within a vein. A pipe viscometry apparatus was employed to obtain a rheological model of 1% polidocanol foams across shear rates of 6 s -1 to 400 s -1 . Two different foam formulation techniques (double syringe system and Tessari) and three liquid-to-gas ratios (1:3, 1:4 and 1:5) were investigated. A power-law model was employed on the rheological data to obtain the apparent viscosity of foams. In a separate experiment, a finite volume of foam was injected into a PTFE tube to displace a blood surrogate solution (0.2% w / v carboxymethyl cellulose). The displaced blood surrogate was collected, weighed, and correlated with foam's apparent viscosity. Results showed a decreasing displacement efficacy with foam dryness and injection flowrate. Furthermore, an asymptotic model was formulated that may be used to predict the extent of blood displacement for a given foam formulation and volume. The developed model could guide clinicians in their selection of a foam formulation that exhibits the greatest blood displacement efficacy.

Data on monkeypox in children and adolescents aged <18 years are limited (1,2). During May 17–September 24, 2022, a total of 25,038 monkeypox cases were reported in the United States, † primarily among adult gay, bisexual, and other men who have sex with men (3). During this period, CDC and U.S. jurisdictional health departments identified Monkeypox virus (MPXV) infections in 83 persons aged <18 years, accounting for 0.3% of reported cases. Among 28 children aged 0–12 years with monkeypox, 64% were boys, and most had direct skin-to-skin contact with an adult with monkeypox who was caring for the child in a household setting. Among 55 adolescents aged 13–17 years, most were male (89%), and male-to-male sexual contact was the most common presumed exposure route (66%). Most children and adolescents with monkeypox were non-Hispanic Black or African American (Black) (47%) or Hispanic or Latino (Hispanic) (35%). Most (89%) were not hospitalized, none received intensive care unit (ICU)–level care, and none died. Monkeypox in children and adolescents remains rare in the United States. Ensuring equitable access to monkeypox vaccination, testing, and treatment is a critical public health priority. Vaccination for adolescents with risk factors and provision of prevention information for persons with monkeypox caring for children might prevent additional infections., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Sanfilippo syndrome is a group of rare, complex, and progressive neurodegenerative lysosomal storage disorders that is characterized by childhood dementia. The clinical management of patients with progressive neurological decline and multisystem involvement requires a multidisciplinary team with experience in the management of neurodegenerative disorders. Best practice guidelines for the clinical management of patients with these types of rare disorders are critical to ensure prompt diagnosis and initiation of appropriate care. However, there are no published standard global clinical care guidelines for patients with Sanfilippo syndrome. To address this, a literature review was conducted to evaluate the current evidence base and to identify evidence gaps. The findings were reviewed by an international steering committee composed of clinical experts with extensive experience in managing patients with Sanfilippo syndrome. The goal was to create a consensus set of basic clinical guidelines that will be accessible to and informed by clinicians globally, as well as providing a practical resource for families to share with their local care team who may not have experience with this rare disease. This review distills 178 guideline statements into an easily digestible document that provides evidence-based, expert-led recommendations for how to approach common management challenges and appropriate monitoring schedules in the care of patients with Sanfilippo syndrome., (© 2022. The Author(s).)

Apathy is the commonest neuropsychiatric symptom in Alzheimer's disease (AD). Previous findings suggest that apathy is caused by a communication breakdown between functional neural networks involved in motivational-affective processing. This study investigated the relationship between white matter (WM) damage and apathy in AD. Sixty-one patients with apathy (AP-PT) and 61 without apathy (NA-PT) were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and matched for cognitive status, age and education. Sixty-one cognitively unimpaired (CU) participants were also included as controls. Data on cognitive performance, cerebrospinal fluid biomarkers, brain/WM hyperintensity volumes and diffusion tensor imaging indices were compared across groups. No neurocognitive differences were found between patient groups, but the AP-PT group had more severe neuropsychiatric symptoms. Compared with CU participants, only apathetic patients had deficits on the Clock Drawing Test. AP-PT had increased WM damage, both macrostructurally, i.e., larger WM hyperintensity volume, and microstructurally, i.e., increased radial/axial diffusivity and reduced fractional anisotropy in the fornix, cingulum, anterior thalamic radiations and superior longitudinal and uncinate fasciculi. AP-PT showed signs of extensive WM damage, especially in associative tracts in the frontal lobes, fornix and cingulum. Disruption in structural connectivity might affect crucial functional inter-network communication, resulting in motivational deficits and worse cognitive decline.

Background: Fully porous acetabular shells are an appealing choice for patients with extensive acetabular defects undergoing revision total hip arthroplasty (rTHA). This study reports on the early outcomes of a novel 3-D printed fully porous titanium acetabular shell in revision acetabular reconstruction., Methods: A multicenter retrospective study of patients who received a fully porous titanium acetabular shell for rTHA with a minimum of 2 years of follow-up was conducted. The primary outcome was rate of acetabular revision., Results: The final study cohort comprised 68 patients with a mean age of 67.6 years (standard deviation 10.4) and body mass index of 29.5 kg/m 2 (standard deviation 5.9). Ninety-four percent had a preoperative Paprosky defect grade of 2A or higher. The average follow-up duration was 3.0 years (range 2.0-5.1). Revision-free survivorship at 2 years was 81% for all causes, 88% for acetabular revisions, and 90% for acetabular revision for aseptic acetabular shell failure. Eight shells were explanted within 2 years (12%): 3 for failure of osseointegration/aseptic loosening (4%) after 15, 17, and 20 months; 3 for infection (4%) after 1, 3, and 6 months; and 2 for instability (3%). At the latest postoperative follow-up, all unrevised shells showed radiographic signs of osseointegration, and none had migrated., Conclusions: This novel 3-D printed fully porous titanium shell in rTHA demonstrated good survivorship and osseointegration when used in complex acetabular reconstruction at a minimum of 2 years., Level of Evidence: IV, case series., (© 2022 The Authors.)