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We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the solar system, exploring the transient optical sky, and mapping the Milky Way. LSST will be a large, wide-field ground-based system designed to obtain repeated images covering the sky visible from Cerro Pachón in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg 2 field of view, a 3.2-gigapixel camera, and six filters (ugrizy) covering the wavelength range 320-1050 nm. The project is in the construction phase and will begin regular survey operations by 2022. About 90% of the observing time will be devoted to a deep-wide-fast survey mode that will uniformly observe a 18,000 deg 2 region about 800 times (summed over all six bands) during the anticipated 10 yr of operations and will yield a co-added map to r ∼27.5. These data will result in databases including about 32 trillion observations of 20 billion galaxies and a similar number of stars, and they will serve the majority of the primary science programs. The remaining 10% of the observing time will be allocated to special projects such as Very Deep and Very Fast time domain surveys, whose details are currently under discussion. We illustrate how the LSST science drivers led to these choices of system parameters, and we describe the expected data products and their characteristics.

H Nothnagel,1–3 M Brown Menard4,5, G Kvarstein,6 AJ Norheim,3 T Weiss,7 C Puta1,8, SD Mist,9 F Musial31Department of Sports Medicine and Health Promotion, Friedrich Schiller University Jena, Jena, Germany; 2Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany; 3Department of Community Medicine, The National Research Center for Complementary and Alternative Medicine (NAFKAM), UiT The Arctic University of Norway, Tromsø, Norway; 4Crocker Institute, Kiawah Island, SC, USA; 5School of Integrative Medicine and Health Sciences, Saybrook University, Oakland, CA, USA; 6Pain clinic, University Hospital of Northern Norway, UiT The Arctic University of Norway, Tromsø, Norway; 7Department of Biological and Clinical Psychology, Friedrich Schiller University, Jena, Germany; 8Center for Interdisciplinary Prevention of Diseases related to Professional Activities, Friedrich Schiller University, Jena, Germany; 9Oregon Health & Science University, Portland, OR, USABackground: Recruitment and inclusion procedures in clinical trials are time critical. This holds particularly true for studies investigating patients with fluctuating symptom patterns, like those with chronic neck pain. In a feasibility study on neck pain, we found a clinically relevant decrease in pain ratings within the recruitment period. This paper analyses the phenomenon and gives recommendations for recruitment procedures in clinical trials on pain.Methods: Changes in pain intensity scores of 44 chronic neck pain patients (6 males and 36 females; mean age: 45.3±13.2 years) between the first telephone contact and baseline assessment were analyzed. Inclusion criterion was a mean pain intensity of ≥40 on a 0–100 numerical rating scale during the last three months. Statistical analyses were performed using ANOVA and parametric/non-parametric correlation coefficients.Results: Average pain intensity score decreased significantly from 60.3±13.3 at telephone interview to 38.1±21.7 at baseline assessment. This represents a relative change of 36.8%. A weak but significant negative correlation was found between number of days between assessments and pain rating differences. There was a positive correlation between change of pain intensity and the pain level at the first contact, indicating that the decreased pain ratings over time were also dependent on the initial pain rating.Conclusions: The clinically significant changes in pain intensity were weakly related to waiting time and moderately dependent on initial pain intensity, suggesting regression to the mean. The natural course of the disease and the Hawthorne effect are also discussed as contributing factors.Keywords: chronic neck pain, Hawthorne effect, natural course of the disease, regression to the mean, clinical trial, recruitment

Abstract Background Breast cancer outcome, including response to therapy, risk of metastasis and survival, is difficult to predict using currently available methods, highlighting the urgent need for more informative biomarkers. Androgen receptor (AR) has been implicated in breast carcinogenesis however its potential to be an informative biomarker has yet to be fully explored. In this study, AR protein levels were determined in a cohort of 73 Grade III invasive breast ductal adenocarcinomas. Methods The levels of Androgen receptor protein in a cohort of breast tumour samples was determined by immunohistochemistry and the results were compared with clinical characteristics, including survival. The role of defects in the regulation of Androgen receptor gene expression were examined by mutation and methylation screening of the 5' end of the gene, reporter assays of the 5' and 3' end of the AR gene, and searching for miRNAs that may regulate AR gene expression. Results AR was expressed in 56% of tumours and expression was significantly inversely associated with 10-year survival (P = 0.004). An investigation into the mechanisms responsible for the loss of AR expression revealed that hypermethylation of the AR promoter is associated with loss of AR expression in breast cancer cells but not in primary breast tumours. In AR negative breast tumours, mutation screening identified the same mutation (T105A) in the 5'UTR of two AR negative breast cancer patients but not reported in the normal human population. Reporter assay analysis of this mutation however found no evidence for a negative impact on AR 5'UTR activity. The role of miR-124 in regulating AR expression was also investigated, however no evidence for this was found. Conclusion This study highlights the potential for AR expression to be an informative biomarker for breast cancer survival and sets the scene for a more comprehensive investigation of the molecular basis of this phenomenon.

Abstract Background Iron acquisition systems are important virulence factors in pathogenic bacteria. To identify these systems in Acinetobacter baumannii, the transcriptomic response of the completely sequenced strain ATCC 17978 under iron limiting conditions was investigated using a genomic microarray that contained probes for all annotated open reading frames. Results Under low iron conditions, transcription levels were more than 2-fold up-regulated for 463 genes, including 95 genes that were up-regulated more than 4-fold. Of particular significance, three siderophore biosynthesis gene clusters, including one novel cluster, were highly up-regulated. Binding sites for the ferric uptake regulator were identified in the promoter regions of many up-regulated genes, suggesting a prominent role for this regulator in the Acinetobacter iron acquisition response. Down-regulation under iron limitation was less dramatic as the transcription of only 202 genes varied more than 2-fold. Various genes involved in motility featured prominently amongst the genes down-regulated when iron was less readily available. Motility assays confirmed that these transcriptional changes are manifested at the phenotypic level. The siderophore biosynthesis gene clusters were further investigated by means of comparative genomic analysis of 10 sequenced Acinetobacter isolates. These analyses revealed important roles for mobile genetic elements in shaping the siderophore meditated iron acquisition mechanisms between different Acinetobacter strains. Conclusions A. baumannii grown under iron limited conditions resulted in major transcriptional changes of not only many iron acquisition related genes, but also genes involved in other processes such as motility. Overall, this study showed that A. baumannii is well adaptable to growth in an environment which has limiting iron availability.

Abstract Background Genetic screening of breast cancer patients and their families have identified a number of variants of unknown clinical significance in the breast cancer susceptibility genes, BRCA1 and BRCA2. Evaluation of such unclassified variants may be assisted by web-based bioinformatic prediction tools, although accurate prediction of aberrant splicing by unclassified variants affecting exonic splice enhancers (ESEs) remains a challenge. Methods This study used a combination of RT-PCR analysis and splicing reporter minigene assays to assess five unclassified variants in the BRCA2 gene that we had previously predicted to disrupt an ESE using bioinformatic approaches. Results Analysis of BRCA2 c.8308 G > A (p.Ala2770Thr) by mRNA analysis, and BRCA2 c.8962A > G (p.Ser2988Gly), BRCA2 c.8972G > A (p.Arg2991His), BRCA2 c.9172A > G (p.Ser3058Gly), and BRCA2 c.9213G > T (p.Glu3071Asp) by a minigene assay, revealed no evidence for aberrant splicing. Conclusions These results illustrate the need for improved methods for predicting functional ESEs and the potential consequences of sequence variants contained therein.

Abstract Background Gamma motor neurons (γ-MNs) selectively innervate muscle spindle intrafusal fibers and regulate their sensitivity to stretch. They constitute a distinct subpopulation that differs in morphology, physiology and connectivity from α-MNs, which innervate extrafusal muscle fibers and exert force. The mechanisms that control the differentiation of functionally distinct fusimotor neurons are unknown. Progress on this question has been limited by the absence of molecular markers to specifically distinguish and manipulate γ-MNs. Recently, it was reported that early embryonic γ-MN precursors are dependent on GDNF. Using this knowledge we characterized genetic strategies to label developing γ-MNs based on GDNF receptor expression, showed their strict dependence for survival on muscle spindle-derived GDNF and generated an animal model in which γ-MNs are selectively lost. Results In mice heterozygous for both the Hb9::GFP transgene and a tau-lacZ-labeled (TLZ) allele of the GDNF receptor Gfrα1, we demonstrated that small motor neurons with high Gfrα1-TLZ expression and lacking Hb9::GFP display structural and synaptic features of γ-MNs and are selectively lost in mutants lacking target muscle spindles. Loss of muscle spindles also results in the downregulation of Gfrα1 expression in some large diameter MNs, suggesting that spindle-derived factors may also influence populations of α-MNs with β-skeletofusimotor collaterals. These molecular markers can be used to identify γ-MNs from birth to the adult and to distinguish γ- from β-motor axons in the periphery. We also found that postnatal γ-MNs are also distinguished by low expression of the neuronal nuclear protein (NeuN). With these markers of γ-MN identity, we show after conditional elimination of GDNF from muscle spindles that the survival of γ-MNs is selectively dependent on spindle-derived GDNF during the first 2 weeks of postnatal development. Conclusion Neonatal γ-MNs display a unique molecular profile characterized by the differential expression of a series of markers - Gfrα1, Hb9::GFP and NeuN - and the selective dependence on muscle spindle-derived GDNF. Deletion of GDNF expression from muscle spindles results in the selective elimination of γ-MNs with preservation of the spindle and its sensory innervation. This provides a mouse model with which to explore the specific role of γ-fusimotor activity in motor behaviors.

Abstract Background The staphylococcal QacA multidrug efflux protein confers resistance to an exceptional number of structurally unrelated antimicrobial compounds. Aromatic amino acid residues have been shown to be highly important for the transport function of several multidrug transporters and are intimately involved in multidrug binding. This study investigated the structural and functional importance of the seven tyrosine residues in QacA by examining the phenotypic effect of incorporating conservative (aromatic) and non-conservative (non-aromatic) substitutions for these residues. Results Determination of the resistance profiles and analysis of drug transport assays revealed that non-conservative substitutions for most tyrosine residues influenced the QacA drug recognition spectrum. However, an aromatic residue at three tyrosine positions, 63, 410 and 429, was of importance for QacA-mediated transport and resistance to the majority of substrates tested. Conclusion A tyrosine or phenylalanine residue at amino acid positions corresponding to 63 of QacA in related drug efflux proteins is found to be highly conserved. Therefore, an aromatic side chain at this position is likely to partake in a function common to these drug transporters, such as proton translocation or essential intramolecular contacts, whereas aromatic residues at the non-conserved 410 and 429 positions are expected to mediate a QacA-specific function, possibly forming or stabilising part of the QacA drug binding region.

The developing mammalian heart undergoes an important metabolic shift from glycolysis towards mitochondrial oxidation that is critical to support the increasing energetic demands of the maturing heart. Here, we describe a new mechanistic link between mitochondria and cardiac morphogenesis, uncovered by studying mitochondrial citrate carrier (SLC25A1) knockout mice. Slc25a1 null embryos displayed impaired growth, mitochondrial dysfunction and cardiac malformations that recapitulate the congenital heart defects observed in 22q11.2 deletion syndrome, a microdeletion disorder involving the SLC25A1 locus. Importantly, Slc25a1 heterozygous embryos, while overtly indistinguishable from wild type, exhibited an increased frequency of these defects, suggesting Slc25a1 haploinsuffiency and dose-dependent effects. Mechanistically, SLC25A1 may link mitochondria to transcriptional regulation of metabolism through epigenetic control of gene expression to promote metabolic remodeling in the developing heart. Collectively, this work positions SLC25A1 as a novel mitochondrial regulator of cardiac morphogenesis and metabolic maturation, and suggests a role in congenital heart disease., (© 2024. The Author(s).)

Functional loss of the motor protein, Myosin Vb (MYO5B), induces various defects in intestinal epithelial function and causes a congenital diarrheal disorder, microvillus inclusion disease (MVID). Utilizing the MVID model mice, Vil1-Cre ERT2 ;Myo5b flox/flox (MYO5B∆IEC) and Vil1-Cre ERT2 ;Myo5b flox/G519R (MYO5B(G519R)), we previously reported that functional MYO5B loss disrupts progenitor cell differentiation and enterocyte maturation that result in villus blunting and deadly malabsorption symptoms. In this study, we determined that both absence and a point mutation of MYO5B impair lipid metabolism and alter mitochondrial structure, which may underlie the progenitor cell malfunction observed in MVID intestine. Along with a decrease in fatty acid oxidation, the lipogenesis pathway was enhanced in the MYO5B∆IEC small intestine. Consistent with these observations in vivo , RNA-sequencing of enteroids generated from the two MVID mouse strains showed similar downregulation of energy metabolic enzymes, including mitochondrial oxidative phosphorylation genes. In our previous studies, lysophosphatidic acid (LPA) signaling ameliorates epithelial cell defects in MYO5B∆IEC tissues and enteroids. The present study demonstrated that the highly soluble LPAR5-preferred agonist, Compound-1, improved sodium transporter localization and absorptive function, and tuft cell differentiation in patient-modeled MVID animals that carry independent mutations in MYO5B. Body weight loss in male MYO5B(G519R) mice was ameliorated by Compound-1. These observations suggest that Compound-1 treatment has a trophic effect on intestine with MYO5B functional loss through epithelial cell-autonomous pathways that can accelerate the differentiation of progenitor cells and the maturation of enterocytes. Targeting LPAR5 may represent an effective therapeutic approach for treatment of MVID symptoms induced by different point mutations in MYO5B.

Study Design: This study was a retrospective propensity-matched study of patients receiving opioid sparing anesthesia (OSA) and those who did not receive an opioid sparing anesthesia regimen., Objectives: To determine whether patients undergoing spine fusion for deformity fared better with an OSA regimen than those not having an OSA regimen., Summary of Background Data: There has been a tremendous focus on opioid overuse. Accordingly, OSA regimens are being introduced to reduce narcotic use. However, OSA has not been studied in the adult spine deformity population., Methods: 43 patients undergoing fusion of at least five levels in the thoracolumbar spine received OSA. They were matched to 43 patients who did receive an OSA regimen. We analyzed a number of metrics including blood loss, anesthesia time, post anesthesia care unit (PACU) pain scores, postoperative pain scores, complications, length of stay, and readmissions., Results: The OSA group had significantly lower pain scores both before transfer to (4.6 vs. 7.6, P=0.000) and after transfer from (4.2 vs. 6.2 P=0.002) the PACU. Opioid use was significantly lower in the OSA group (454 vs. 241 MMEs by POD4, P=0.022). Fewer patients required blood transfusion in the OSA (1 vs. 28, P=0.000) group. Fewer patients in the OSA group had constipation and urinary retention (1 vs. 9, P=0.015). There was no difference in discharge home or to a facility. The lengths of hospital (4.33 vs. 6.19, P=0.009) and ICU (0.12 vs. 0.70 days, P=0.009) stay were significantly shorter in the OSA group., Conclusion: OSA regimens have numerous benefits in patients undergoing spinal deformity surgery including less opioid use, fewer postoperative complications, and a reduced length of stay., Competing Interests: Authors have no conflicts of interest to declare related to the subject of the manuscript., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Functional loss of the motor protein, Myosin Vb (MYO5B), induces various defects in intestinal epithelial function and causes a congenital diarrheal disorder, microvillus inclusion disease (MVID). Utilizing the MVID model mice, Vil1-Cre ERT2 ;Myo5b flox/flox (MYO5BΔIEC) and Vil1-Cre ERT2 ;Myo5b flox/G519R (MYO5B(G519R)), we previously reported that functional MYO5B loss disrupts progenitor cell differentiation and enterocyte maturation that result in villus blunting and deadly malabsorption symptoms. In this study, we determined that both absence and a point mutation of MYO5B impair lipid metabolism and alter mitochondrial structure, which may underlie the progenitor cell malfunction observed in MVID intestine. Along with a decrease in fatty acid oxidation, the lipogenesis pathway was enhanced in the MYO5BΔIEC small intestine. Consistent with these observations in vivo , RNA-sequencing of enteroids generated from two MVID mouse strains showed similar downregulation of energy metabolic enzymes, including mitochondrial oxidative phosphorylation genes. In our previous studies, lysophosphatidic acid (LPA) signaling ameliorates epithelial cell defects in MYO5BΔIEC tissues and enteroids. The present study demonstrates that the highly soluble LPAR5-preferred agonist, Compound-1, improved sodium transporter localization and absorptive function, and tuft cell differentiation in patient-modeled MVID animals that carry independent mutations in MYO5B. Body weight loss in male MYO5B(G519R) mice was ameliorated by Compound-1. These observations suggest that Compound-1 treatment has a trophic effect on intestine with MYO5B functional loss through epithelial cell-autonomous pathways that may improve the differentiation of progenitor cells and the maturation of enterocytes. Targeting LPAR5 may represent an effective therapeutic approach for treatment of MVID symptoms induced by different point mutations in MYO5B., New & Notewothy: This study demonstrates the importance of MYO5B for cellular lipid metabolism and mitochondria in intestinal epithelial cells, a previously unexplored function of MYO5B. Alterations in cellular metabolism may underlie the progenitor cell malfunction observed in microvillus inclusion disease (MVID). To examine the therapeutic potential of progenitor-targeted treatments, the effects of LPAR5-preferred agonist, Compound-1, was investigated utilizing several MVID model mice and enteroids. Our observations suggests that Compound-1 may provide a therapeutic approach for treating MVID.

Introduction Although transforaminal interbody fusion (TLIF) and anterior lumbar interbody fusion (ALIF) combined with posterior fusion (AP) have similar fusion rates, it is unclear if choice of approach has an impact on post-operative complications. Research question Is the incidence of residual leg and/or back pain requiring additional treatment after one- or two-level TLIF and AP similar? Material and methods Adult patients who underwent one- or two-level TLIF or AP for degenerative pathology were identified and matched using age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA), insurance status, smoking status, revision and number of levels fused. The incidence of radicular leg and back pain requiring emergency department visit/readmission or same level surgical intervention was compared between the two groups. Results Of the 319 TLIF and 288 AP cases, 119 cases in each cohort were matched. TLIF patients had shorter operative times (203 min vs 258 min, P<0.001) and hospital stays than the AP patients (3.76 days vs 4.98 days, P<0.001). The incidence of residual leg pain (7 vs 5, P=0.769) and back pain (13 vs 15, P=0.841) was similar between the two groups. Except for constipation, which was more common in the AP group, the incidence of complications was similar between the two groups. Conclusions Patients undergoing one- or two-level TLIF showed shorter operative time and hospital stay compared with those undergoing AP. The incidence of leg radiculopathy and back pain was similar between the two groups. Surgeons should consider these findings as part of the decision-making process regarding which approach to use in patients requiring a lumbar interbody fusion., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. University of Louisville Institutional Review Board issued approval 21.0840. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Glassman, Brown, Daniels, Djurasovic, Gum, Carreon declare(s) a grant from Alan L. & Jacqueline B. Stuart Spine Research, Scoliosis Research Society, Biom'up, Cerapedics, Inc, Empirical Spine Inc, Medtronic, National Spine Health Foundation, Stryker. Funds to institution. Glassman declare(s) personal fees from K2M / Stryker, Medtronic, Proprio, DePuy. Gum declare(s) personal fees from Consulting: Acuity, DePuy, FYR, Medtronic, NuVasive, Stryker, Baxter, Broadwater, MiMedx, Pacira Pharmaceuticals . Gum declare(s) royalties from Acuity, Medtronic, NuVasive. Gum declare(s) stock/stock options from Cingulate Therapeutics . Djurasovic declare(s) personal fees and royalties from Medtronic, NuVasive. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nagata et al.)

Food systems comprise interconnected webs of processes that together transform inputs (land, labour, water, nutrients and genetics, to mention just a few) into outputs such as nutrition and revenue for human societies. Perfect systems do not exist; rather, global food systems operate in the presence of hazards, biotic and abiotic alike, and under the constraint of limited resources to mitigate these hazards. There are, therefore, inefficiencies in these systems, which lead to losses in terms of monetary, nutritional, health and environmental values and create additional negative externalities in the health, social and environmental spaces. Health hazards in the food system do not respect arbitrary distinctions between the crop and livestock sectors, which are highly interconnected. These linkages exist where one sector provides inputs to another or through substitution effects where supply in one sector influences demand in another. The One Health approach advocates investigating the intersectoral hazards in a highly interdisciplinary manner. This article provides a conceptual framework for integrating the methodologies developed by the Global Burden of Crop Loss and Global Burden of Animal Diseases initiatives to generate burden estimates for hazards in food systems that better account for interconnectivity and foster an improved understanding of food systems that is aligned with the interdisciplinary nature of the One Health approach. A case study related to maize and poultry sector linkages in the wider context of public and environmental health is presented.

Histone deacetylase (HDAC) inhibitors are a widely recognized and valued treatment option for patients with relapsed or refractory peripheral T cell lymphomas (PTCL). Romidepsin is a relatively selective Class I HDAC inhibitor originally approved for patients with relapsed or refractory (R/R) cutaneous T cell lymphoma (CTCL) and subsequently R/R PTCL. Unfortunately, the FDA approval of romidepsin for R/R PTCL was withdrawn due to a negative Phase 4 post-marketing requirement (PMR), diminishing further the treatment options for patients with PTCL. Herein we describe the development of a first-in-class polymer nanoparticle of romidepsin (Nanoromidepsin) using an innovative amphiphilic di-block copolymer-based nanochemistry platform. Nanoromidepsin exhibited superior pharmacologic disposition, with improved tolerability and safety in murine models of T-cell lymphoma. Nanoromidepsin also exhibited superior anti-tumor efficacy in multiple models including in vitro T cell lymphoma (TCL) cell lines, ex vivo LGL leukemia primary patient samples, and murine TCL xenografts. Nanoromidepsin demonstrated greater accumulation in tumors and a statistically significant improvement in overall survival (OS) compared to romidepsin in murine xenograft models. These findings collectively justify the clinical development of Nanoromidepsin in patients with T-cell malignancies.

Aims/hypothesis: Immunotherapeutics targeting T cells are crucial for inhibiting autoimmune disease progression proximal to disease onset in type 1 diabetes. A growing number of T cell-directed therapeutics have demonstrated partial therapeutic efficacy, with anti-CD3 (α-CD3) representing the only regulatory agency-approved drug capable of slowing disease progression through a mechanism involving the induction of partial T cell exhaustion. There is an outstanding need to augment the durability and effectiveness of T cell targeting by directly restraining proinflammatory T helper type 1 (Th1) and type 1 cytotoxic CD8 + T cell (Tc1) subsets, while simultaneously augmenting regulatory T cell (Treg) activity. Here, we present a novel strategy for reducing diabetes incidence in the NOD mouse model using a blocking monoclonal antibody targeting the type 1 diabetes-risk associated T cell co-stimulatory receptor, CD226., Methods: Female NOD mice were treated with anti-CD226 between 7-8 weeks of age and then monitored for diabetes incidence and therapeutic mechanism of action., Results: Compared to isotype-treated controls, anti-CD226 treated NOD mice showed reduced insulitis severity at 12 weeks and decreased disease incidence at 30 weeks. Flow cytometric analysis performed five weeks post-treatment demonstrated reduced proliferation of CD4 + and CD8 + effector memory T cells in spleens of anti-CD226 treated mice. Phenotyping of pancreatic Tregs revealed increased CD25 expression and STAT5 phosphorylation following anti-CD226, with splenic Tregs displaying augmented suppression of CD4 + T cell responders in vitro. Anti-CD226 treated mice exhibited reduced frequencies of islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP)-reactive CD8 + T cells in the pancreas, using both ex vivo tetramer staining and single-cell T cell receptor sequencing (scTCR-seq) approaches. 51 Cr-release assays demonstrated reduced cell-mediated lysis of beta-cells by anti-CD226-treated autoreactive cytotoxic T lymphocytes., Conclusions/interpretation: CD226 blockade reduces T cell cytotoxicity and improves Treg function, representing a targeted and rational approach for restoring immune regulation in type 1 diabetes., Competing Interests: Duality of Interest: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

Objective: Anterior approaches to the lumbar spine have been used extensively for various indications but they are also associated with unique complications and have been linked with higher incisional morbidity.This study aimsto evaluate incisional morbidity related to anterior lumbar surgeries and to assess how incisional outcomes correlate with patient and surgery-related factors., Methods: Patients ≥18 years old and with planned anterior lumbar fusions from L1 to S1 were prospectively enrolled. Follow-up ended at two years, and patients who did not complete the follow-up were excluded. Incision was assessed for general appearance, width, color, cross-hatching, hypertrophy, and pain by using a validated scoring system and a visual analog scale (VAS). Patient and surgery-related factors were analyzed for possible correlations with complications or wound-related parameters., Results: A total of 205 patients with a mean age of 54.4 ± 11.5 were included. Significant improvements were seen in color, hypertrophy, pain, and appearance of the incision. At two years, the mean patient-based VAS for appearance was 8.6 while surgeon-based VAS was 8.8. The total rate of complications was 9%, with no incisional hernia or bulging. No significant relation was found between incision-related parameters and the demographic and surgical variables., Conclusion: This study reports acceptable cosmetic results and no chronic pain after anterior lumbar surgery, which is contrary to previous reports. Together with a low total rate of complications, anterior approaches are safe when carefully executed, and have low morbidity., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. University of Louisville Institutional Review Board issued approval HSPPO#14.0567/RO#14.N0125. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: John R. Dimar II declare(s) personal fees from Depuy. John R. Dimar II declare(s) personal fees from Stryker. John R. Dimar II declare(s) personal fees from Icotec. John R. Dimar II, Leah Y. Carreon, Morgan E. Brown, Christy L. Daniels declare(s) a grant from Scoliosis Research Society. Grant to Institution. John R. Dimar II, Leah Y. Carreon, Morgan E. Brown, Christy L. Daniels declare(s) a grant from Alan L. & Jacqueline B. Stuart Spine Research. Grant to Institution. John R. Dimar II, Leah Y. Carreon, Morgan E. Brown, Christy L. Daniels declare(s) a grant from Biom'Up. Grant to Institution. John R. Dimar II, Leah Y. Carreon, Morgan E. Brown, Christy L. Daniels declare(s) a grant from Cerapedics. Grant to Institution. John R. Dimar II, Leah Y. Carreon, Morgan E. Brown, Christy L. Daniels declare(s) a grant from Empirical Spine. Grant to Institution. John R. Dimar II, Leah Y. Carreon, Morgan E. Brown, Christy L. Daniels declare(s) a grant from Medtronic. Grant to Institution. John R. Dimar II, Leah Y. Carreon, Morgan E. Brown, Christy L. Daniels declare(s) a grant from National Spine Health Foundation. Grant to Institution. John R. Dimar II, Leah Y. Carreon, Morgan E. Brown, Christy L. Daniels declare(s) a grant from Stryker. Grant to Institution. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Cetik et al.)

Background : Access to safe, effective, and appropriate contraception significantly reduces the rates of unintended pregnancies; however, this preventative care is not always easily accessible. There is a high patient demand for contraception visits that is often delayed or unmet due to lack of access to traditional providers. Pharmacists are highly accessible and can help manage this high demand, yet clinical pharmacists as providers of contraception services remains a gap in published literature. Objective : Develop and implement a pharmacist-led contraception service at a safety-net health-system. Methods : A comprehensive pharmacist-led clinical contraception service was created to improve patient access. To support this project, a collaborative practice agreement (CPA) was developed and enhancements were built into an electronic medical record. The CPA allowed the pharmacist to complete contraception-related interventions such as ordering urine pregnancy tests, prescribing hormonal and emergency contraceptives, and manage adverse effects. The piloting pharmacist was available at the Narcotics Treatment Program (NTP) clinic one half-day each week for scheduled and same-day visits. Results : Within the initial five half-day clinic sessions at NTP, the pharmacist had written seven prescriptions, including three for emergency contraceptives. Of all patients seen for this service at NTP, only one had been using a method of contraception consistently prior to their visit. Conclusion : The interventions that were able to be made by the pharmacist highlighted the need for improved access to contraceptives. Pharmacist-managed services in sexual and reproductive health can help fill this gap. Patients also self-reported ease of access as a benefit to this service., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Hypoimmune gene edited human pluripotent stem cells (hPSCs) are a promising platform for developing reparative cellular therapies that evade immune rejection. Existing first-generation hypoimmune strategies have used CRISPR/Cas9 editing to modulate genes associated with adaptive (e.g., T cell) immune responses, but have largely not addressed the innate immune cells (e.g., monocytes, neutrophils) that mediate inflammation and rejection processes occurring early after graft transplantation. We identified the adhesion molecule ICAM-1 as a novel hypoimmune target that plays multiple critical roles in both adaptive and innate immune responses post-transplantation. In a series of studies, we found that ICAM-1 blocking or knock-out (KO) in hPSC-derived cardiovascular therapies imparted significantly diminished binding of multiple immune cell types. ICAM-1 KO resulted in diminished T cell proliferation responses in vitro and in longer in vivo retention/protection of KO grafts following immune cell encounter in NeoThy humanized mice. The ICAM-1 KO edit was also introduced into existing first-generation hypoimmune hPSCs and prevented immune cell binding, thereby enhancing the overall hypoimmune capacity of the cells. This novel hypoimmune editing strategy has the potential to improve the long-term efficacy and safety profiles of regenerative therapies for cardiovascular pathologies and a number of other diseases., Competing Interests: Conflict of Interest Disclosure M.E.B is a consultant for Taconic Biosciences, and is an inventor on a patent application filed by WARF related to this work. The other authors declare no conflict of interest.

Purpose: Wet age-related macular degeneration (AMD) is a blinding retinal disease. Monthly intravitreal anti-VEGF antibody injections of bevacizumab (off-label) and ranibizumab (FDA approved) are the standard of care. Antibody aggregation may interfere with ocular absorption/distribution. This study assessed topical delivery of dilute antibodies to the posterior segment of rabbit eyes using a novel anti-aggregation formula (AAF)., Methods: Bevacizumab, or biosimilar ranibizumab was diluted to 5 mg/ml in AAF. All rabbits were dosed twice daily. Substudy 1 rabbits (bevacizumab, 100 µl eye drops): Group 1 (bevacizumab/AAF, n = 6); Group 2 (bevacizumab/PBS, n = 7) and Vehicle control (AAF, n = 1). Substudy 2 rabbits (ranibizumab biosimilar/AAF, 50 µl eye drops): (ranibizumab biosimilar/AAF, n = 8). At 14.5 days, serum was drawn from rabbits. Aqueous, vitreous and retina samples were recovered from eyes and placed into AAF aliquots. Tissue analyzed using AAF as diluent., Results: Bevacizumab in AAF permeated/accumulated in rabbit aqueous, vitreous and retina 10 times more, than when diluted in PBS. AAF/0.1% hyaluronic acid eye drops, dosed twice daily, provided mean tissue concentrations (ng/g) in retina (29.50), aqueous (12.34), vitreous (3.46), and serum (0.28 ng/ml). Additionally, the highest concentration (ng/g) of ranibizumab biosimilar was present in the retina (18.0), followed by aqueous (7.82) and vitreous (1.47). Serum concentration was negligible (< 0.04 ng/ml). No irritation was observed throughout the studies., Conclusions: Bevacizumab and ranibizumab, in an AAF diluent eye drop, can be delivered to the retina, by the twice daily dosing of a low concentration mAb formulation. This may prove to be an adjunct to intravitreal injections., (© 2024. The Author(s).)

Study Design: Retrospective single-center study using prospectively collected data., Objective: To describe the incidence of and identify risk factors for intraoperative screw malposition secondary to skive or shift during robot-assisted cortical bone trajectory (RA-CBT) insertion., Summary of Background Data: RA-CBT screw malposition occurs through 2 distinct modes, skive or shift. Skive occurs when a downward force applied to the cannula, drill, tap, or screw, causes the instrument to deflect relative to its bony landmark. Shift is a change in the position of the RA system relative to the patient after registration., Patients and Methods: A consecutive series of patients older than 18 years who underwent RA-CBT screw placement between January 2019 and July 2022 were enrolled. Baseline demographic and surgical data, Hounsfield Units (HUs) at L1, and vertebral shape related to screw planning were collected. Skive or shift was recorded in the operating room on a data collection form., Results: Of 1344 CBT screws in 256 patients, malposition was recognized intraoperatively in 33 screws (2.4%) in 27 patients (10.5%); 19 through skive in 17 and 14 through shift in 10 patients. These patients had higher body mass index than patients without malposition (33.0 vs. 30.5 kg/m 2 , P = 0.037). Patients with skive had higher HU (178.2 vs . 145.2, P = 0.035), compared with patients with shift (139.2 vs . 145.2, P = 0.935) and patients without screw malposition. More than half of the screw malposition was observed at the upper instrumented vertebra. At the upper instrumented vertebra, if the screw's overlap to the bone surface at the insertion point was decreased, skive was more likely (57% vs . 87%, P < 0.001). No patients were returned to the operating room for screw revision., Conclusions: Intraoperative screw malposition occurred in 2.4% of RA-CBT. High body mass index was associated with screw malposition, regardless of etiology. Skive was associated with high HU and decreased screw overlap to the bone surface at the insertion point., Competing Interests: J.L.G receives consulting fees from Depuy, Medtronic, NuVasive, K2M/Stryker; royalties from Acuity, Medtronic on robotic specific projects, NuVasive. S.D.G. receives consulting fees from Depuy, Medtronic and K2M/Stryker. S.D.G., M.E.B., C.L.D., L.Y.C., B.H., and J.L.G.—institution receives funding from Alan L. and Jacqueline B. Stuart Spine Research Foundation, Cerapedics, Biom’Up, Empirical Spine, Scoliosis Research Society, Stryker, TSRH, Medtronic. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Asteroids with diameters less than about 5 km have complex histories because they are small enough for radiative torques (that is, YORP, short for the Yarkovsky-O'Keefe-Radzievskii-Paddack effect) 1 to be a notable factor in their evolution 2 . (152830) Dinkinesh is a small asteroid orbiting the Sun near the inner edge of the main asteroid belt with a heliocentric semimajor axis of 2.19 AU; its S-type spectrum 3,4 is typical of bodies in this part of the main belt 5 . Here we report observations by the Lucy spacecraft 6,7 as it passed within 431 km of Dinkinesh. Lucy revealed Dinkinesh, which has an effective diameter of only 720 m, to be unexpectedly complex. Of particular note is the presence of a prominent longitudinal trough overlain by a substantial equatorial ridge and the discovery of the first confirmed contact binary satellite, now named (152830) Dinkinesh I Selam. Selam consists of two near-equal-sized lobes with diameters of 210 m and 230 m. It orbits Dinkinesh at a distance of 3.1 km with an orbital period of about 52.7 h and is tidally locked. The dynamical state, angular momentum and geomorphologic observations of the system lead us to infer that the ridge and trough of Dinkinesh are probably the result of mass failure resulting from spin-up by YORP followed by the partial reaccretion of the shed material. Selam probably accreted from material shed by this event., (© 2024. The Author(s).)

Background: Cost, efficiency, patient preference, and safety have driven utilization of wide awake, local anesthesia, no tourniquet (WALANT) in hand surgery. This is not well documented in adolescents. We hypothesize that the use of WALANT with adolescents reduced time spent in the operating room (OR) and in the hospital when compared with patients who underwent surgery with traditional anesthesia (TA)., Methods: After institutional review board approval, we performed a retrospective review of patients aged 10 to 17 who underwent surgery at a regional hospital system including the level 1 pediatric trauma hospital. Operative notes were assessed for use of WALANT. We excluded those operations not traditionally amenable to WALANT. Using a propensity matched cohort, hospital time, OR time, and perioperative complications were recorded and compared to evaluate efficiency and perioperative safety., Results: There were 28 cases in the WALANT group and 28 cases in the TA group after excluding cases not amenable to WALANT, and cases were propensity matched. Although the operative time (incision to closure) was similar, for WALANT patients, the in-room to procedure time (15 vs 22 minutes), procedure end to out-room time (5 vs 10 minutes), total room time (52.81 vs 63.68), and length of hospital stay (222 vs 342 minutes) were shorter than patients in the TA group., Conclusion: Our case series demonstrates time-savings both in the OR and in the hospital overall. Avoiding TA when WALANT is feasible may result in significant savings to hospital systems, patients, and payers while also freeing up anesthesia staff and perioperative nurses., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Pancreatic ductal adenocarcinoma (PDAC) presents at advanced stages and is refractory to most treatment modalities. Wnt signaling activation plays a critical role in proliferation and chemotherapeutic resistance. Minimal media conditions, growth factor dependency, and Wnt dependency were determined via Wnt inhibition for seven patient derived organoids (PDOs) derived from pancreatic tumor organoid libraries (PTOL). Organoids demonstrating response in vitro were assessed in vivo using patient-derived xenografts. Wnt (in)dependent gene signatures were identified for each organoid. Panc269 demonstrated a trend of reduced organoid growth when treated with ETC-159 in combination with paclitaxel or gemcitabine as compared with chemotherapy or ETC-159 alone. Panc320 demonstrated a more pronounced anti-proliferative effect in the combination of ETC-159 and paclitaxel but not with gemcitabine. Panc269 and Panc320 were implanted into nude mice and treated with ETC-159, paclitaxel, and gemcitabine as single agents and in combination. The combination of ETC-159 and paclitaxel demonstrated an anti-tumor effect greater than ETC-159 alone. Extent of combinatory treatment effect were observed to a lesser extent in the Panc320 xenograft. Wnt (in)dependent gene signatures of Panc269 and 320 were consistent with the phenotypes displayed. Gene expression of several key Wnt genes assessed via RT-PCR demonstrated notable fold change following treatment in vivo. Each pancreatic organoid demonstrated varied niche factor dependencies, providing an avenue for targeted therapy, supported through growth analysis following combinatory treatment of Wnt inhibitor and standard chemotherapy in vitro. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. Gene expression analysis suggests there are key Wnt genes that contribute to the Wnt (in)dependent phenotypes of pancreatic tumors, providing plausible mechanistic explanation for Wnt (in)dependency and susceptibility or resistance to treatment on the genotypic level., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hawkins 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.)

Genetically diverse simian arteriviruses (simarteriviruses) naturally infect geographically and phylogenetically diverse monkeys, and cross-species transmission and emergence are of considerable concern. Characterization of most simarteriviruses beyond sequence analysis has not been possible because the viruses fail to propagate in the laboratory. We attempted to isolate 4 simarteriviruses, Kibale red colobus virus 1, Pebjah virus, simian hemorrhagic fever virus, and Southwest baboon virus 1, by inoculating an immortalized grivet cell line (known to replicate simian hemorrhagic fever virus), primary macaque cells, macrophages derived from macaque induced pluripotent stem cells, and mice engrafted with macaque CD34+-enriched hematopoietic stem cells. The combined effort resulted in successful virus isolation; however, no single approach was successful for all 4 simarteriviruses. We describe several approaches that might be used to isolate additional simarteriviruses for phenotypic characterization. Our results will expedite laboratory studies of simarteriviruses to elucidate virus-host interactions, assess zoonotic risk, and develop medical countermeasures.

Although aggression occurs across a range of disorders, associations between dimensions of psychopathology and self- and other-directed aggression are not well understood. Investigating associations between psychopathology dimensions and aggression helps further understanding about the etiology of aggression, and ultimately, can inform intervention and prevention strategies. This study adopted a multi-method approach to examine associations between internalizing and externalizing dimensions of psychopathology and self- and other-directed aggression as a function of reporter (participant and informant) and modality of aggression measurement (subjective and objective). Participants were an unselected sample of 151 racially diverse adults recruited from the community. Dimensions of psychopathology were assessed using interview and questionnaire reports from participants and collateral informants, and forms of aggression were measured via subjective reports and an objective, laboratory aggression paradigm. Analyses of participant-reported psychological symptom data consistently linked externalizing symptoms to other-directed aggression, and internalizing symptoms to self-directed aggression. Results across informant and participant reporters replicated prior findings showing a significant interaction between internalizing and externalizing dimensions in predicting intimate partner violence. Most other effects in informant models were nonsignificant. The findings uncover consistency in and replicability of relationships between dimensions of psychopathology and certain manifestations of aggression and highlight the importance of examining multiple forms of aggression in etiological research. Examining aggression through a transdiagnostic lens can help us better understand and intervene upon processes implicated in devasting forms of self- and other-directed aggression., (© 2024 The Authors. Aggressive Behavior published by Wiley Periodicals LLC.)

Background: Sustaining evidence-based practices (EBPs) is crucial to ensuring care quality and addressing health disparities. Approaches to identifying factors related to sustainability are critically needed. One such approach is Matrixed Multiple Case Study (MMCS), which identifies factors and their combinations that influence implementation. We applied MMCS to identify factors related to the sustainability of the evidence-based Collaborative Chronic Care Model (CCM) at nine Department of Veterans Affairs (VA) outpatient mental health clinics, 3-4 years after implementation support had concluded., Methods: We conducted a directed content analysis of 30 provider interviews, using 6 CCM elements and 4 Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) domains as codes. Based on CCM code summaries, we designated each site as high/medium/low sustainability. We used i-PARIHS code summaries to identify relevant factors for each site, the extent of their presence, and the type of influence they had on sustainability (enabling/neutral/hindering/unclear). We organized these data into a sortable matrix and assessed sustainability-related cross-site trends., Results: CCM sustainability status was distributed among the sites, with three sites each being high, medium, and low. Twenty-five factors were identified from the i-PARIHS code summaries, of which 3 exhibited strong trends by sustainability status (relevant i-PARIHS domain in square brackets): "Collaborativeness/Teamwork [Recipients]," "Staff/Leadership turnover [Recipients]," and "Having a consistent/strong internal facilitator [Facilitation]" during and after active implementation. At most high-sustainability sites only, (i) "Having a knowledgeable/helpful external facilitator [Facilitation]" was variably present and enabled sustainability when present, while (ii) "Clarity about what CCM comprises [Innovation]," "Interdisciplinary coordination [Recipients]," and "Adequate clinic space for CCM team members [Context]" were somewhat or less present with mixed influences on sustainability., Conclusions: MMCS revealed that CCM sustainability in VA outpatient mental health clinics may be related most strongly to provider collaboration, knowledge retention during staff/leadership transitions, and availability of skilled internal facilitators. These findings have informed a subsequent CCM implementation trial that prospectively examines whether enhancing the above-mentioned factors within implementation facilitation improves sustainability. MMCS is a systematic approach to multi-site examination that can be used to investigate sustainability-related factors applicable to other EBPs and across multiple contexts., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Study Design: Retrospective chart review., Objective: To provide reference values for Hounsfield unit (HU) measured on computed tomography (CT) scans of children and adolescents., Summary of Background Data: Spine surgeons increasingly use HU on spine CT as a measure of bone mineral density (BMD). This has not been described in children and adolescents., Patients and Methods: Pediatric patients who had a spine CT between 2012 and 2022 were identified. Patients who had more than 1 comorbidity or were syndromic were excluded. Using the bone window, 3 axial images (cephalad, middle, and caudal) of each vertebra were selected. In each axial view, the HU was measured using a "region of interest" (ROI) that included the total cancellous bone area and an ROI excluding the radiolucency present in the posterior vertebral body ("total" vs . "limited"). HU values were compared between total and limited areas and between the axial images at the cephalad, middle, and caudal levels. Each age category data were estimated and stratified., Results: A total of 144 patients (79 females and 65 males) from 2 to 17 years old were included. Mean limited HU was consistently lower than total HU across all images and lumbar levels except for L1. Limited HU taken mid-vertebral body was also consistently lower than those taken cephalad or caudad. Mean limited HU across all ages including all levels was 227 ± 50 (range: 109-357). Stratifying by age showed a gradual decrease in BMD from age 2 to 10 followed by an increase., Conclusions: This is the first study to measure HU on lumbar CTs in children and adolescents. The technique of measuring BMD in adults should be modified in children by using an ROI that excludes the rarefaction present in the posterior vertebral body. Further studies are needed to evaluate the age-dependent changes in BMD seen in this study., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)