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Acute vascular injury provokes an inflammatory response, resulting in neointimal hyperplasia (NIH) and downstream pathologies. The resolution of inflammation is an active process in which specialized proresolving lipid mediators (SPM) and their receptors play a central role. We sought to examine the acute phase response of SPM and their receptors in both circulating blood and the arterial wall in a rat angioplasty model. We found that the ratio of proresolving to pro-inflammatory lipid mediators (LM) in plasma decreased sharply 1 day after vascular injury, then increased slightly by day 7, while that in arteries remained depressed. Granulocyte expression of SPM receptors ALX/FPR2 and DRV2/GPR18, and a leukotriene B4 receptor BLT1 increased postinjury, while ERV1/ChemR23 expression was reduced early and then recovered by day 7. Importantly, we show unique arterial expression patterns of SPM receptors in the acute setting, with generally low levels through day 7 that contrasted sharply with that of the pro-inflammatory CCR2 receptor. Overall, these data document acute, time-dependent changes of LM biosynthesis and SPM receptor expression in plasma, leukocytes, and artery walls following acute vascular injury. A biochemical imbalance between inflammation and resolution LM pathways appears persistent 7 days after angioplasty in this model. These findings may help guide therapeutic approaches to accelerate vascular healing and improve the outcomes of vascular interventions for patients with advanced atherosclerosis.

BackgroundSpecialized pro-resolving lipid mediators (SPM) such as resolvin D1 (RvD1) attenuate inflammation and exhibit vasculo-protective properties.MethodsWe investigated poly-lactic-co-glycolic acid (PLGA)-based nanoparticles (NP), containing a peptide targeted to tissue factor (TF) for delivery of 17R-RvD1 and a synthetic analog 17-R/S-benzo-RvD1 (benzo-RvD1) using in vitro and in vivo models of acute vascular injury. NPs were characterized in vitro by size, drug loading, drug release, TF binding, and vascular smooth muscle cell migration assays. NPs were also characterized in a rat model of carotid angioplasty.ResultsPLGA NPs based on a 75/25 lactic to glycolic acid ratio demonstrated optimal loading (507.3 pg 17R-RvD1/mg NP; P = ns) and release of RvD1 (153.1 pg 17R-RvD1/mg NP; P < .05). NPs incorporating the targeting peptide adhered to immobilized TF with greater avidity than NPs with scrambled peptide (50 nM: 41.6 ± 0.52 vs 32.66 ± 0.34; 100 nM: 35.67 ± 0.95 vs 23.5 ± 0.39; P < .05). NPs loaded with 17R-RvD1 resulted in a trend toward blunted vascular smooth muscle cell migration in a scratch assay. In a rat model of carotid angioplasty, 16-fold more NPs were present after treatment with TF-targeted NPs compared with scrambled NPs (P < .01), with a corresponding trend toward higher tissue levels of 17R-RvD1 (P = .06). Benzo-RvD1 was also detectable in arteries treated with targeted NP delivery and accumulated at 10 times higher levels than NP loaded with 17R-RvD1. There was a trend toward decreased CD45 immunostaining in vessels treated with NP containing benzo-RvD1 (0.76 ± 0.38 cells/mm2 vs 122.1 ± 22.26 cells/mm2; P = .06). There were no significant differences in early arterial inflammatory and cytokine gene expression by reverse transcription-polymerase chain reaction.ConclusionsTF-targeting peptides enhanced NP-mediated delivery of SPM to injured artery. TF-targeted delivery of SPMs may be a promising therapeutic approach to attenuate the vascular injury response.

Abstract Background Rates of penicillin allergy mislabeling (PAM) are prevalent and lead to suboptimal antibiotic selection. However, data regarding PAM are lacking for people with HIV (PWH). We aimed to characterize the penicillin allergy labels for PWH at the University of California, San Diego’s (UCSD) HIV primary care clinic, evaluate the impact of penicillin allergy labels on treatment choice for syphilis and gonorrhea, and implement a quality improvement project to address PAM. Methods We conducted a cross-sectional study of PWH with a penicillin allergy label in their medical record who were seen in our clinic between 2018 and 2022. We collected demographic information, type of allergic reaction listed, whether patients tolerated other beta-lactam antibiotics, whether patients were referred for formal Allergy consultation, and, where relevant, what treatment they received for syphilis and/or gonorrhea. Results Among the 4,702 people with HIV receiving care in our clinic between 2018 and 2022, 427 (9.1%) had a penicillin allergy label in the medical record. This cohort reflected the demographics of the general clinic population (Table 1). Even though the majority of allergic reactions (327, 77%) were labeled as IgE-mediated, 282 (66%) patients tolerated another beta-lactam antibiotic (Table 2). Referrals to Allergy Clinic were rare (52, 12%). The majority of patients with syphilis (91/140, 65%) received 2nd line therapy with doxycycline. However, most patients with gonorrhea (65/88, 74%) were treated with a preferred ceftriaxone-based regimen. When relevant, we updated penicillin labels for 209/268 (77.9%) patients to indicate that they had tolerated other beta-lactam antibiotics and created a tiered referral process to prioritize the highest-risk patients for Allergy Clinic referral (Figure 1). Conclusion Penicillin allergy labels were prevalent in our cohort of PWH and often resulted in receiving 2nd line therapy for treatment of syphilis. We updated allergy labels for a substantial number of patients and created a triage system to refer patients to Allergy clinic for further testing based on risk in order to decrease PAM. Disclosures All Authors: No reported disclosures.

Background:. The study investigated the expectations of patients undergoing immediate breast reconstruction after mastectomy, considering factors such as the cause for mastectomy (cancer versus prophylactic due BRCA1 or BRCA2 gene mutations), age, marital status, and education. Methods:. The study had a cross-sectional design. Eligible patients at Oslo University Hospital received a link to the BREAST-Q Expectations questionnaire, which they filled out before surgery from 2019 to 2022. Results:. One hundred forty-six patients completed the questionnaire (79.8% response rate). The mean age was 46.6 years, and the majority (95.1%) were undergoing reconstruction with implants. Most patients (86.9%) wanted to be involved in the decision-making. The highest expectation was for breast appearance and the lowest for sensation after surgery. Patients not diagnosed with cancer (n = 27) before surgery expected significantly more pain after surgery compared with patients diagnosed with cancer (P = 0.016). Patients 40 years or younger had higher expectation of pain after surgery than patients 41 years or older, 73.2 versus 54.2, P < 0.001, respectively. After 10 years, 26.7% of the patients expected that further reconstruction procedures might be necessary. Conclusions:. Our study’s results regarding patient’s expectations with breast reconstruction, as assessed using the BREAST-Q Expectations module, align with previous research in terms of overall trends. However, our study provides a more nuanced understanding by exploring variations within different patient subgroups. These differences emphasize the need for personalized preoperative counseling and support to align patient’s expectations with realistic outcomes.

IntroductionThis study describes perceived knowledge gaps of third-year medical students after participating in a virtual surgical didactic rotation (EMLR) and shortened in-person surgery rotation during the COVID-19 Pandemic.MethodsOpen-ended and Likert questions were administered at the end of the virtual rotation and inperson-surgical rotation to medical students. Three blinded coders identified themes by semantic analysis.Results82 students (51% of all MS3s) participated in the EMLR. Semantic analysis revealed gaps in perioperative management (Post-EMLR:18.4%, Post-Inpatient:26.5%), anatomy (Post-EMLR:8.2%, PostInpatient:26.5%). and surgical skills (Post-EMLR: 43.0%, Post-Inpatient: 44.1%). Students also described gaps related to OR etiquette (Post-EMLR: 12.2%, Post-Inpatient: 8.8%) and team dynamics/the hidden curriculum (Post- Inpatient:26.6%). There was a significant improvement in perceived confidence to perform inpatient tasks after completing the inpatient clinical experience (p ≤ 0.01).ConclusionVirtual interactive didactics for cognitive skills development cannot replace a full clinical surgical experience for third-year medical students. Future curricula should address perceived gaps.

BackgroundPersistent inflammation following vascular injury drives neointimal hyperplasia (NIH). Specialized lipid mediators (SPM) mediate resolution which attenuates inflammation and downstream NIH. We investigated the effects of a synthetic analogue of resolvin D1 (RvD1) on vascular cells and in a model of rat carotid angioplasty.MethodsHuman venous VSMC and endothelial cells (EC) were employed in migration, cell shape, toxicity, proliferation and p65 nuclear translocation assays. Murine RAW 264.7 cells were utilized to test the effect of pro-resolving compounds on phagocytic activity. A model of rat carotid angioplasty was used to evaluate the effects of 17R/S-benzo-RvD1 (benzo-RvD1) and 17R-RvD1 applied to the adventitia via 25% Pluronic gel. Immunostaining was utilized to examine Ki67 expression and leukocyte recruitment. Morphometric analysis was performed on arteries harvested 14 days after injury.ResultsExposure to benzo-RvD1 attenuated PDGF- stimulated VSMC migration across a range of concentrations (0.1-100 nM), similar to that observed with 17R-RvD1. Pre-treatment with either Benzo-RvD1 or 17R-RvD1 (10, 100nM) attenuated PDGF-BB-induced VSMC cytoskeletal changes to nearly baseline dimensions. Benzo-RvD1 demonstrated modest anti-proliferative activity on VSMC and EC at various concentrations, without significant cytotoxicity. Benzo-RvD1 (10nM) inhibited p65 nuclear translocation in cytokine-stimulated EC by 21% (p

IntroductionThe impact of COVID-19 on surgical education has been profound, and clinical learning experiences transitioned to virtual formats. This study investigated the impact of virtual experiences created to facilitate learning during the pandemic for medical students.MethodsWe performed a cohort study to determine the perceived clinical preparedness for medical students enrolled in the preclinical surgery pilot course, surgical Extended Mastery Learning Rotation (EMLR), and longitudinal surgical clerkship (LC). The preclinical surgery pilot course took place before COVID-19 disruptions, and the EMLR and LC experiences took place virtually. Specialty choice was examined in the EMLR and LC cohorts. Performance on the NBME surgical assessments was analyzed among students enrolled in the traditional clerkship and pandemic-disrupted courses and compared to national data using a two-sample t-test.ResultsCompared to preclinical students, EMLR and LC students demonstrated improvements in their perceived surgical clerkship readiness. After the 3-week EMLR course, in the setting of completing only one-third of the clerkship year, students had an average NBME Surgical Self-Assessment Exam score of 72 (SD 12), comparable to the national average of 71 (SD 9) p = 0.33. The average shelf exam score for students (N = 24) enrolled in the traditional clerkship (block 1), prior to COVID-19, disruptions was 66 (SD 9) compared to an average score of 69 (SD 9) for the longitudinal clerkship students (N = 20) that took the shelf exam later in the year (p = 0.36). COVID-19 disruptions did not affect specialty choice. All LC students have decided on a specialty; 50% nonsurgical and 50% surgical. From the EMLR cohort, 36% and 38% plan to pursue surgical and nonsurgical specialties, respectively, with 26% still undecided.ConclusionsCourses were well-liked and will be implemented in future clerkships. Surgical educators demonstrated flexibility and creativity in the development of the EMLR. Despite COVID-19 disruptions, medical students made progress in their clinical skills and foundational science knowledge. COVID-19 disruptions did not appear to impact specialty choice.

Ti-doped In 2 O 3 thin films with varying Ti contents are prepared by partial reactive co-sputtering using ceramic In 2 O 3 and metallic Ti targets and characterized by in situ x-ray photoelectron spectroscopy, electrical conductivity, and Hall-effect measurements. For a substrate temperature of 400 ° C , the carrier concentration increases faster than the Ti content and saturates at ≈ 7.4 × 10 20 c m − 3 . Based on these results, it is suggested that Ti does not directly act as donor in In 2 O 3 but is rather forming TiO 2 precipitates and that the related scavenging of oxygen generates oxygen vacancies in In 2 O 3 as origin of doping. Neutralization of oxygen vacancies is, therefore, suggested to be origin of the limitation of the carrier concentration in Ti-doped In 2 O 3 films. [ABSTRACT FROM AUTHOR]

PROBLEM: The COVID-19 pandemic has suspended the surgery clinical clerkship for third-year medical students at numerous institutions across the world. As a result, educators and students have adapted rapidly. There is a paucity of precedents regarding urgent and brusque formal curricular changes for medical students enrolled in surgical clinical rotations. APPROACH: The University of California, San Francisco Department of Surgery created a surgically focused extended mastery learning rotation (EMLR). The surgery clerkship leadership designed a curriculum consisting of multiple learning strategies compatible with virtual learning environments. The primary aims of the newly developed EMLR were to help students consolidate their foundational science knowledge before their return to clinical medicine in an altered learning environment. The EMLR is currently underway, and further studies are necessary to evaluate its effectiveness.

Persistent inflammation is the key aggravator in many cardiovascular diseases, including atherosclerosis, aneurysm, injury/reperfusion, thrombosis, and neointimal hyperplasia following surgical or percutaneous interventions. Resolution is an active process orchestrated by specialized pro-resolving lipid mediators (SPMs) which tamp down acute inflammatory signals, promote healing and facilitate a return to homeostasis. SPMs are endogenously derived from poly-unsaturated fatty acids, and their biologic activity is mediated via specific G-protein coupled receptor binding. The potency of SPM in regulating the inflammatory response has encouraged investigation into their therapeutic and diagnostic use in cardiovascular pathologies. Herein we describe the translational groundwork which has established the synthesis and interactions of SPM in cardiovascular and hematologic cells, the therapeutic effects of SPM in animal models of cardiovascular disease, and some early technologies that harness and attempt to optimize SPM delivery and "resolution pharmacology". Further studies are required to precisely determine the mechanisms of resolution in the cardiovascular system and to determine the clinical settings in which SPM can be utilized to optimize patient outcomes.

Background:. Several western countries have experienced a drastic increase of referrals to specialist gender services of transgender and gender-diverse people. Chest wall contouring is an important element in treatment of gender dysphoria. National data concerning this group have yet to be investigated. The aim of this study was to examine and evaluate the techniques and surgical outcome of chest wall contouring from the last 20 years from a single center in Norway. Methods:. This study is a retrospective review of all female-to-male patients who underwent chest wall contouring surgery at Oslo University Hospital between 2000 and 2020. Statistical analysis with comparison of techniques and evaluation of development over time was examined. Results:. In total, 333 patients underwent bilateral chest wall contouring, 209 (62.8%) with inframammary incision with free nipple graft (IM), and 124 (37.2%) with periareolar technique (PA). In 20 years, the average age decreased from 31 (19–68) to 24.9 years (17–61). Average body mass index was significantly lower in the PA-group than in the IM-group. Complication rate was 20.7%, with postoperative bleeding being the most frequent (9.6%). Revision surgery was required in 24.9% of the cases; periareolar technique required significantly more procedures. Conclusions:. The number of patients referred and operated on has increased drastically over a 20-year period. When comparing the techniques, the outcome concerning complications and revisions is at an acceptable level. Postoperative bleeding and revision surgery occur more often with the periareolar technique. There remains a knowledge gap concerning quality of life and satisfaction after surgery within this patient group.

Background/Objectives: Cone dystrophy with supernormal rod response (CDSRR) is a rare autosomal recessive retinal disorder characterized by a delayed and markedly decreased photoreceptor response. In this article, we aim to describe the clinical course and associated molecular findings in children with cone dystrophy with supernormal rod response associated with recessive mutations in the KCNV2 gene, which encodes a subunit (Kv8.2) of the voltage-gated potassium channel. Methods: The genetic testing of two patients included the next-generation sequencing of a retinal dystrophy panel and direct Sanger sequencing to confirm KCNV2 gene variants, in addition to an electroretinogram (ERG) and spectral domain optical coherence tomography (SD-OCT). Results: Cone dystrophy with supernormal rod response is associated with identified variants in the KCNV2 gene. The genetic analysis of the first case identified a compound heterozygous mutation in the KCNV2 gene, including a de novo nonsense duplication at cDNA position 1109, which led to the premature termination of the p.Lys371Ter codon in the second extracellular domain of the protein. Two patients showed changes in the full-field electroretinogram, especially in the first case, which demonstrated a close to supernormal total electroretinogram amplitude. This study increased the range of the KCNV2 mutation database, added an unreported de novo substitution pattern to KCNV2 gene variants, and linked it to the evaluated clinical studies. Conclusions: The initial clinical manifestations were varied, but both patients presented with hypermetropia and slight exotropia. The ERG findings are characteristic of KCNV2 mutations, and patients exhibited an increased b-wave latency in DA3.0 ERG (combined rod–cone response). [ABSTRACT FROM AUTHOR]

Objective: To document the impact of early follow-up by specialized cleft nurses (SCNs) to families of infants with cleft lip and/or cleft palate (CL/P). Design: Prospective inclusion of a control group, which received standard care alone, followed by an intervention group, which in addition received early SCN follow-up. Setting: The cleft lip and palate team at a University hospital. Participants: 70 families (69 mothers and 57 fathers); control group (n = 38); intervention group (n = 32). Intervention: SCNs offered a consultation at the maternity ward and follow-ups by phone or face-to-face at one, three, eight weeks and six months after birth. Outcome measures: Use of Internet-Questionnaire, Quality of discharge teaching scale (QDTS), Post discharge coping difficulty scale (PDCDS), Response on follow-up by health professionals. Results: Infants in the intervention group were admitted less frequently to a Neonatal Intensive Care unit (NICU); 21.9% vs 51.4%, P =.012. Parents in the intervention group used internet for cleft-related reasons less frequently (74.6% vs 85.9%), P =.112 and the mothers benefitted less from cleft-related activity on the internet (P =.013). The intervention group reported higher mean score for satisfaction with total cleft care (P =.001). There were no significant group differences regarding mean total score for discharge teaching (P =.315) and coping difficulties (P =.919). Conclusion: Early follow-up by a SCN with expertise in cleft care is highly valued by parents. Closer cooperation between the cleft team and health professionals at birth hospitals and Child health centers is necessary for optimal follow-up. [ABSTRACT FROM AUTHOR]

How are the advantage relations between a set of agents playing a game organized and how do they reflect the structure of the game? In this paper, we illustrate 'Principal Trade-off Analysis' (PTA), a decomposition method that embeds games into a low-dimensional feature space. We argue that the embeddings are more revealing than previously demonstrated by developing an analogy to Principal Component Analysis (PCA). PTA represents an arbitrary two-player zero-sum game as linear combination of simple games via the projection of policy profiles into orthogonal 2D feature planes. We show that the feature planes represent unique strategic trade-offs and truncation of the sequence provides insightful model reduction and visualization. We demonstrate the validity of PTA on a quartet of games (Kuhn poker, RPS + 2, Blotto and Pokemon). In Kuhn poker, PTA clearly identifies the trade-off between bluffing and calling. In Blotto, PTA identifies game symmetries and specifies strategic trade-offs associated with distinct win conditions. These symmetries reveal limitations of PTA unaddressed in previous work. For Pokemon, PTA recovers clusters that naturally correspond to Pokemon types, correctly identifies the designed trade-off between those types, and discovers a rock-paper-scissor (RPS) cycle in the Pokemon generation type – all absent any specific information except game outcomes. [ABSTRACT FROM AUTHOR]

NKG2D is an important immunoreceptor expressed on the surface of NK cells and some T cells. NKG2D recognizes a set of ligands typically expressed on infected or transformed cells, but recent studies have also documented NKG2D ligands on subsets of host non-tumor cells in tumor-bearing animals and humans. Here we show that in transplanted tumors and genetically engineered mouse cancer models, tumor-associated macrophages are induced to express the NKG2D ligand RAE-1δ. We find that a soluble factor produced by tumor cells is responsible for macrophage RAE-1δ induction, and we identify tumor-derived colony-stimulating factor-1 (CSF-1) as necessary and sufficient for macrophage RAE-1δ induction in vitro and in vivo. Furthermore, we show that induction of RAE-1δ on macrophages by CSF-1 requires PI3K p110α kinase signaling. Thus, production of CSF-1 by tumor cells leading to activation of PI3K p110α represents a novel cellular and molecular pathway mediating NKG2D ligand expression on tumor-associated macrophages.

NKG2D is an important immunoreceptor expressed on the surface of NK cells and some T cells. NKG2D recognizes a set of ligands typically expressed on infected or transformed cells, but recent studies have also documented NKG2D ligands on subsets of host non-tumor cells in tumor-bearing animals and humans. Here we show that in transplanted tumors and genetically engineered mouse cancer models, tumor-associated macrophages are induced to express the NKG2D ligand RAE-1δ. We find that a soluble factor produced by tumor cells is responsible for macrophage RAE-1δ induction, and we identify tumor-derived colony-stimulating factor-1 (CSF-1) as necessary and sufficient for macrophage RAE-1δ induction in vitro and in vivo. Furthermore, we show that induction of RAE-1δ on macrophages by CSF-1 requires PI3K p110α kinase signaling. Thus, production of CSF-1 by tumor cells leading to activation of PI3K p110α represents a novel cellular and molecular pathway mediating NKG2D ligand expression on tumor-associated macrophages.

Natural Killer (NK) cells confer protection from tumors and infections by releasing cytotoxic granules and pro-inflammatory cytokines upon recognition of diseased cells. The responsiveness of NK cells to acute stimulation is dynamically tuned by steady-state receptor-ligand interactions of an NK cell with its cellular environment. Here, we demonstrate that in healthy WT mice the NK activating receptor NKG2D is engaged in vivo by one of its ligands, RAE-1ε, which is expressed constitutively by lymph node endothelial cells and highly induced on tumor-associated endothelium. This interaction causes internalization of NKG2D from the NK cell surface and transmits an NK-intrinsic signal that desensitizes NK cell responses globally to acute stimulation, resulting in impaired NK antitumor responses in vivo.

Natural Killer (NK) cells confer protection from tumors and infections by releasing cytotoxic granules and pro-inflammatory cytokines upon recognition of diseased cells. The responsiveness of NK cells to acute stimulation is dynamically tuned by steady-state receptor-ligand interactions of an NK cell with its cellular environment. Here, we demonstrate that in healthy WT mice the NK activating receptor NKG2D is engaged in vivo by one of its ligands, RAE-1ε, which is expressed constitutively by lymph node endothelial cells and highly induced on tumor-associated endothelium. This interaction causes internalization of NKG2D from the NK cell surface and transmits an NK-intrinsic signal that desensitizes NK cell responses globally to acute stimulation, resulting in impaired NK antitumor responses in vivo.