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Abstract Dendritic cells (DCs) are crucial for initiating protective immune responses and have also been implicated in the generation and regulation of Foxp3+ regulatory T cells (Treg cells). Here, we show that in the lamina propria of the small intestine, the alternative NF-κB family member RelB is necessary for the differentiation of cryptopatch and isolated lymphoid follicle-associated DCs (CIA-DCs). Moreover, single-cell RNA sequencing reveals a RelB-dependent signature in migratory DCs in mesenteric lymph nodes favoring DC-Treg cell interaction including elevated expression and release of the chemokine CCL22 from RelB-deficient conventional DCs (cDCs). In line with the key role of CCL22 to facilitate DC-Treg cell interaction, RelB-deficient DCs have a selective advantage to interact with Treg cells in an antigen-specific manner. In addition, DC-specific RelB knockout animals show increased total Foxp3+ Treg cell numbers irrespective of inflammatory status. Consequently, DC-specific RelB knockout animals fail to mount protective Th2-dominated immune responses in the intestine after infection with Heligmosomoides polygyrus bakeri. Thus, RelB expression in cDCs acts as a rheostat to establish a tolerogenic set point that is maintained even during strong type 2 immune conditions and thereby is a key regulator of intestinal homeostasis.

Abstract Introduction Biologic therapies are licensed for both psoriasis (PsO) and psoriatic arthritis (PsA) with some electronic medical record data suggest that IL (Interleukin)-23 blockers might be more protective in PsA prevention than TNF blockers; however, the findings have been inconsistent. Higher Psoriasis Area and Severity Index (PASI) scores have also been linked to an increased PsA risk. To clarify these unresolved issues we investigated biologic agents, methotrexate, phototherapy, and topical therapy for PsA prevention in patients with psoriasis. Methods This retrospective cohort study analyzed data from 58,671 patients with psoriasis from the Israeli Meuhedet Health Services Organization database was evaluated for incident PsA. Patients were categorized on the basis of treatment: group 1, topical therapy; group 2, phototherapy; group 3, conventional disease-modifying antirheumatic drugs (cDMARDs; methotrexate); group 4, biologic DMARDs which was also stratified according to biologic class. Results The PsA incidence rate was lower in the biologic agents’ group versus the methotrexate group (HR 0.46 [95% CI 0.35–0.62]). The incidence rates per 100 person-years varied across biologic treatment groups, with the anti‑IL‑12/23 or anti‑IL‑23p19 group at 4.57, the anti-IL-17 group at 4.35, and the TNF inhibitor group at 2.55. No differences were found between various biological agents in terms of preventing PsA. The phototherapy group exhibited a higher PsA development rate than the topical therapy group (HR 1.85 [95% CI 1.65–2.07]). Conclusion Biological agents are more effective than methotrexate in reducing incident PsA in patients with psoriasis. This lower rate of PsA on topical therapy compared to phototherapy supports the importance of psoriasis severity as a risk factor.

Abstract Background In patients with prostate cancer (PCa), imaging with gastrin-releasing peptide receptor (GRPR) ligands is an alternative to PSMA-targeted tracers, particularly if PSMA expression is low or absent. [99mTc]Tc-N4-BTG is a newly developed GRPR-directed probe for conventional scintigraphy and single photon emission computed tomography (SPECT) imaging. The current study aims to investigate the safety, biodistribution and dosimetry of [99mTc]Tc-N4-BTG in patients with biochemical recurrence (BCR) of PCa. Results No adverse pharmacologic effects were observed. Injection of [99mTc]Tc-N4-BTG resulted in an effective dose of 0.0027 ± 0.0002 mSv/MBq. The urinary bladder was the critical organ with the highest mean absorbed dose of 0.028 ± 0.001 mGy/MBq, followed by the pancreas with 0.0043 ± 0.0015 mGy/MBq, osteogenic cells with 0.0039 ± 0.0005 mGy/MBq, the kidneys with 0.0034 ± 0.0003 mGy/MBq, and the liver with 0.0019 ± 0.0004 mGy/MBq, respectively. No focal tracer uptake suggestive of PCa recurrence could be revealed for any of the patients. Conclusion [99mTc]Tc-N4-BTG appears to be a safe diagnostic agent. Compared to GRPR-targeted PET tracers, this 99mTc-labelled SPECT agent could contribute to a broader application and better availability of this novel approach. Further research to assess its clinical value is warranted.

Abstract Sustainable and effective means to control flying insect vectors are critically needed, especially with widespread insecticide resistance and global climate change. Understanding and controlling vectors requires accurate information about their movement and activity, which is often lacking. The Photonic Fence (PF) is an optical system that uses machine vision, infrared light, and lasers to identify, track, and interdict vectors in flight. The PF examines an insect’s outline, flight speed, and other flight parameters and if these match those of a targeted vector species, then a low-power, retina-safe laser kills it. We report on proof-of-concept tests of a large, field-sized PF (30 mL × 3 mH) conducted with Aedes aegypti, a mosquito that transmits dangerous arboviruses, and Diaphorina citri, a psyllid which transmits the fatal huanglongbing disease of citrus. In tests with the laser engaged,

Metals plates and screws are the gold standard in metacarpal and phalangeal fracture fixation as they provide high stability to complex fractures. However, incidence rates of complications ranging from 42 to 92 % have been reported. Bone bioadhesive fixation based on light-cured thiol-ene technology and reinforced with hydroxyapatite (HA) is a promising solution for customizable devices with tailored mechanical properties and reduced soft tissue adhesion. The reinforcement of these thiol-ene composites with 2D textiles or meshes has been proposed; however, their role in the mechanical performance has not been explored. In this study, structural and mechanical behavior properties of a light-cured resin composite with thiol-ene precursors and HA in the presence and absence of one and three-layer of poly(ethylene terephthalate) (PET) meshes were assessed. The lack of effect of the meshes on the light-cure efficiency and the structural homogeneity of the cured composite is shown using Raman spectroscopy, water uptake measurements, and micro-computed tomography. The insertion of meshes increased the strength and energy to fracture of resin-based composite. The woven geometry of the PET meshes enables frictional sliding behavior, and reduced crack propagation ensuring integrity after matrix failure. This effect increases with the number of meshes and was significantly higher in bending than in tensile stress conditions. Related to hand and wrist fractures, the design of composite fixation devices, based on HA and meshes fillers can significantly increase the strength and toughening of those medical devices with a potential impact on post-operation by reducing mechanical mismatch of stress shielding and prevent complications due to material disintegration, resulting from the compliant and personalized bone bioadhesive fixation application.

Summary: Background: The use of sedation during interventional procedures has continued to rise resulting in increased costs, complications and reduced validity during diagnostic injections, prompting a search for alternatives. Virtual reality (VR) has been shown to reduce pain and anxiety during painful procedures, but no studies have compared it to a control and active comparator for a pain-alleviating procedure. The main objective of this study was to determine whether VR reduces procedure-related pain and other outcomes for epidural steroid injections (ESI). Methods: A randomized controlled trial was conducted in 146 patients undergoing an ESI at 6 hospitals in Thailand and the United States. Patients were allocated to receive immersive VR with local anesthetic, sedation with midazolam and fentanyl plus local anesthetic, or local anesthetic alone. The primary outcome was procedure-related pain recorded on a 0-10 scale. Other immediate-term outcome measures were pain from a standardized subcutaneous skin wheal, procedure-related anxiety, ability to communicate, satisfaction, and time to discharge. Intermediate-term outcome measures at 4 weeks included back and leg pain scores, function, and success defined as a ≥2-point decrease in average leg pain coupled with a score ≥5/7 on a Patient Global Impression of Change scale. Findings: Procedure-related pain scores with both VR (mean 3.7 (SD 2.5)) and sedation (mean 3.2 (SD 3.0)) were lower compared to control (mean 5.2 (SD 3.1); mean differences −1.5 (−2.7, −0.4) and −2.1 (−3.3, −0.9), respectively), but VR and sedation scores did not significantly differ (mean difference 0.5 (−0.6, 1.7)). Among secondary outcomes, communication was decreased in the sedation group (mean 3.7 (SD 0.9)) compared to the VR group (mean 4.1 (SD 0.5); mean difference 0.4 (0.1, 0.6)), but neither VR nor sedation was different than control. The trends favoring sedation and VR over control for procedure-related anxiety and satisfaction were not statistically significant. Post-procedural recovery time was longer for the sedation group compared to both VR and control groups. There were no meaningful intermediate-term differences between groups except that medication reduction was lowest in the control group. Interpretation: VR provides comparable benefit to sedation for procedure-related pain, anxiety and satisfaction, but with fewer side effects, superior communication and a shorter recovery period. Funding: Funded in part by grants from MIRROR, Uniformed Services University of the Health Sciences, U.S. Dept. of Defense, grant # HU00011920011. Equipment was provided by Harvard MedTech, Las Vegas, NV.

BackgroundArtificial intelligence, particularly chatbot systems, is becoming an instrumental tool in health care, aiding clinical decision-making and patient engagement. ObjectiveThis study aims to analyze the performance of ChatGPT-3.5 and ChatGPT-4 in addressing complex clinical and ethical dilemmas, and to illustrate their potential role in health care decision-making while comparing seniors’ and residents’ ratings, and specific question types. MethodsA total of 4 specialized physicians formulated 176 real-world clinical questions. A total of 8 senior physicians and residents assessed responses from GPT-3.5 and GPT-4 on a 1-5 scale across 5 categories: accuracy, relevance, clarity, utility, and comprehensiveness. Evaluations were conducted within internal medicine, emergency medicine, and ethics. Comparisons were made globally, between seniors and residents, and across classifications. ResultsBoth GPT models received high mean scores (4.4, SD 0.8 for GPT-4 and 4.1, SD 1.0 for GPT-3.5). GPT-4 outperformed GPT-3.5 across all rating dimensions, with seniors consistently rating responses higher than residents for both models. Specifically, seniors rated GPT-4 as more beneficial and complete (mean 4.6 vs 4.0 and 4.6 vs 4.1, respectively; P

Posterior cruciate ligament (PCL) ruptures are uncommonly seen in knee ligament injuries. Cconservative treatment is often suitable for isolated tears with mild-to-moderate posterior knee laxity (grades I or II). However, surgical intervention is indicated for symptomatic grade III or multiligament knee injuries. PCL reconstruction has experienced continuous development due to the progress made in arthroscopic techniques and instruments. Abnormal positioning and tensioning of the femoral button result in multiple complications such as residual laxity, loss of quadriceps muscle strength, and joint stiffness. In this Technical Note, we describe direct arthroscopic visualization of the femoral button deployment in PCL reconstruction technique, and we discuss its importance to prevent complications related to button malposition.

The Defense Advanced Research Projects Agency (DARPA) was created in 1958 in response to the Soviet Union's launch of Sputnik. The agency matured in an era of incredible American scientific [...]

Abstract Background Nuclear medicine has made enormous progress in the past decades. However, there are still significant inequalities in patient access among different countries, which could be mitigated by improving access to and availability of radiopharmaceuticals. Main body This paper summarises major considerations for a suitable pharmaceutical regulatory framework to facilitate patient access to radiopharmaceuticals. These include the distinct characteristics of radiopharmaceuticals which require dedicated regulations, considering the impact of the variable complexity of radiopharmaceutical preparation, personnel requirements, manufacturing practices and quality assurance, regulatory authority interfaces, communication and training, as well as marketing authorisation procedures to ensure availability of radiopharmaceuticals. Finally, domestic and regional supply to ensure patient access via alternative regulatory pathways, including in-house production of radiopharmaceuticals, is described, and an outlook on regulatory challenges faced by new developments, such as the use of alpha emitters, is provided. Conclusions All these considerations are an outcome of a dedicated Technical Meeting organised by the IAEA in 2023 and represent the views and opinions of experts in the field, not those of any regulatory authorities.

The University of Maryland, Baltimore County (UMBC) Hyper-Angular Rainbow Polarimeter (HARP2) will be on board NASA's Plankton, Aerosol, Cloud, ocean Ecosystem (PACE) mission, scheduled for launch in January 2024. In this study we systematically evaluate the retrievability and uncertainty of aerosol and ocean parameters from HARP2 multi-angle polarimeter (MAP) measurements. To reduce the computational demand of MAP-based retrievals and maximize data processing throughput, we developed improved neural network (NN) forward models for spaceborne HARP2 measurements over a coupled atmosphere and ocean system within the FastMAPOL retrieval algorithm. To this end, a cascading retrieval scheme is implemented in FastMAPOL, which leverages a series of NN models of varying size, speed, and accuracy to optimize performance. Two sets of NN models are used for reflectance and polarization, respectively. A full day of global synthetic HARP2 data was generated and used to test various retrieval parameters including aerosol microphysical and optical properties, aerosol layer height, ocean surface wind speed, and ocean chlorophyll a concentration. To assess retrieval quality, pixel-wise retrieval uncertainties were derived from error propagation and evaluated against the difference between the retrieval parameters and truth based on a Monte Carlo method. We found that the fine-mode aerosol properties can be retrieved well from the HARP2 data, though the coarse-mode aerosol properties are more uncertain. Larger uncertainties are associated with a reduced number of available viewing angles, which typically occur near the scan edge of the HARP2 instrument. Results of the performance assessment demonstrate that the algorithm is a viable approach for operational application to HARP2 data after the PACE launch.

Background: Suboptimal influenza and pneumococcal vaccination rates have been reported before the COVID-19 pandemics in certain populations at risk for severe infection. The aim of this longitudinal cohort study was to investigate changes in influenza and pneumococcal vaccination rates and patient perceptions in patients with psoriasis (PsO) before and during the pandemic. Methods: Data on vaccination, patient and disease characteristics, comorbidity, and patient perceptions were collected with questionnaires before and during the pandemic approximately one year later. Results: Over the whole cohort who participated in the follow-up visit (n = 287; 59.2% male; mean age: 56.3 years), both influenza and pneumococcal lifetime vaccination prevalences increased significantly from 50.5% to 66.2% and from 16.0% to 41.5%, respectively. A total of 88.5% of PsO patients were interested in a COVID-19 vaccination or had already received it. The reasons for and against vaccinations changed significantly before and during the pandemic. Conclusions: Despite a promising increase in the vaccination prevalence in our PsO cohort, it remains important that awareness for vaccinations is encouraged and closely monitored in future research, particularly in populations at risk.

Study Design This was a randomized double-blind controlled study. Purpose This study was designed to evaluate the effects of intravenous nefopam regarding its ability to reduce morphine consumption and postoperative pain and improve recovery in patients undergoing open spine surgery. Overview of Literature Multimodal analgesia, including nonopioid medications, is essential for pain management in spine surgery. Evidence regarding the use of intravenous nefopam in open spine surgery as part of enhanced recovery after surgery is lacking. Methods In this study, 100 patients undergoing lumbar decompressive laminectomy with fusion were randomized into two groups. The nefopam group received 20-mg intravenous nefopam diluted in 100-mL normal saline intraoperatively, followed by 80-mg nefopam diluted in 500-mL normal saline, administered as a continuous infusion postoperatively for 24 hours. The control group received an identical volume of normal saline. Postoperative pain was managed using intravenous morphine via patient-controlled analgesia. Morphine consumption in the first 24 hours was recorded as the primary outcome. Secondary outcomes, including postoperative pain score, postoperative function, and length of hospital stay (LOS), were assessed. Results No statistically significant differences in the total morphine consumption and postoperative pain score in the first 24 hours postoperatively between the two groups. At the post-anesthesia care unit (PACU), the nefopam group demonstrated lower pain scores while at rest (p=0.03) and upon movement (p=0.02) than the normal saline group. However, the severity of postoperative pain between the two groups was similar from postoperative day 1 to day 3. LOS was significantly shorter in the nefopam group than in the control group (p

Drug repurposing is a strategy for identifying new uses of approved or investigational drugs that are outside the scope of the original medical indication. Even though many repurposed drugs have been found serendipitously in the past, the increasing availability of large volumes of biomedical data has enabled more systemic, data-driven approaches for drug candidate identification. At National Center of Advancing Translational Sciences (NCATS), we invent new methods to generate new data and information publicly available to spur innovation and scientific discovery. In this study, we aimed to explore and demonstrate biomedical data generated and collected via two NCATS research programs, the Toxicology in the 21st Century program (Tox21) and the Biomedical Data Translator (Translator) for the application of drug repurposing. These two programs provide complementary types of biomedical data from uncovering underlying biological mechanisms with bioassay screening data from Tox21 for chemical clustering, to enrich clustered chemicals with scientific evidence mined from the Translator towards drug repurposing. 129 chemical clusters have been generated and three of them have been further investigated for drug repurposing candidate identification, which is detailed as case studies.

Background: The skin–gut axis, characterized by bidirectional communication between the skin and gut, plays a crucial role in the pathogenesis of psoriasis and inflammatory bowel diseases (IBD). Objectives: We aimed to explore the association between psoriasis and IBD and identify predictors associated with IBD development among patients with psoriasis. Design: Retrospective cohort study. Methods: A retrospective study which utilized an electronic database from the Meuhedet Health Maintenance Organization (MHMO) in Israel. Psoriasis was categorized as severe if any systemic agent or phototherapy was administered. Univariate and multivariate logistic regressions were used to identify specific predictors for IBD, with adjustments made for potential confounders. The study received approval from the Ethical Committee of the MHMO. Results: In total, 61,003 adult patients who were diagnosed with psoriasis between 2000 and 2022 were included. Among them, 1495/61,003 patients (2.4%) were diagnosed with IBD, as compared to 3834/244,012 patients (1.6%) in the non-psoriasis group [adjusted odds ratio (OR): 1.47; 95% confidence interval (CI): 1.37–1.56; p

ABSTRACTBackground Because of the high initial cost of intrathecal drug delivery (ITDD) therapy, this study investigated the cost-effectiveness and cost–utility of ITDD therapy in refractory cancer pain management in Thailand over the past 10 years.Methods The retrospective study was conducted in patients with cancer pain who underwent ITDD therapy from January 2011 to 2021 at three university hospitals. Clinical outcomes included the numerical rating scale (NRS), Palliative Performance Scale, and the EQ-5D. The direct medical and nonmedical as well as indirect costs were also recorded. Cost-effectiveness and cost–utility analyses were performed comparing ITDD therapy with conventional therapy (extrapolated from costs of the same patient before ITDD therapy) from a societally oriented economic evaluation.Results Twenty patients (F:M: 10:10) aged 60 ± 15 years who underwent implantation of an intrathecal percutaneous port (IT port; n = 15) or programmable intrathecal pump (IT pump; n = 5) were included. The median survival time was 78 (interquartile range = 121–54) days after ITDD therapy. At 2-month follow-up, the incremental cost-effectiveness ratio (ICER)/pain reduction of an IT port (US$2065.36 (CA$2829.54)/2-point NRS reduction/lifetime) was lower than for patients with an IT pump (US$5479.26 (CA$7506.58)/2-point NRS reduction/lifetime) compared with continued conventional therapy. The ICER/quality-adjusted life years (QALYs) gained for an IT port compared with conventional treatment was US$93,999.31(CA$128,799.06)/QALY gained, which is above the cost-effectiveness threshold for Thailand.Conclusion The cost-effectiveness and cost–utility of IT port therapy for cancer pain was high relative to the cost of living in Thailand, above the cost-effectiveness threshold. Prospective cost analysis studies enrolling more patients with diverse cancers that investigate the benefit of early ITDD therapy with devices over a range of prices are warranted.

Abstract Purpose Patients with unresectable dedifferentiated liposarcoma (DDLPS) have poor overall outcomes. Few genomic alterations have been identified with limited therapeutic options. Experimental Design Patients treated at Levine Cancer Institute with DDLPS were identified. Next generation sequencing (NGS), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) testing were performed on tumor tissue collected at diagnosis or recurrence/progression. Confirmation of genomic alterations was performed by orthologous methods and correlated with clinical outcomes. Univariate Cox regression was used to identify genomic alterations associated with clinical outcomes. Results Thirty‐eight DDLPS patients with adequate tissue for genomic profiling and clinical data were identified. Patient characteristics included: median age at diagnosis (66 years), race (84.2% Caucasian), and median follow‐up time for the entire cohort was 12.1 years with a range from approximately 3.5 months to 14.1 years. Genes involved in cell cycle regulation, including MDM2 (74%) CDK4 (65%), and CDKN2A (23%), were amplified along with WNT/Notch pathway markers: HMGA2, LGR5, MCL1, and CALR (19%–29%). While common gene mutations were identified, PDE4DIP and FOXO3 were also mutated in 47% and 34% of patients, respectively, neither of which have been previously reported. FOXO3 was associated with improved overall survival (OS) (HR 0.37; p = 0.043) along with MAML2 (HR 0.30; p = 0.040). Mutations that portended worse prognosis included RECQL4 (disease‐specific survival HR 4.67; p = 0.007), MN1 (OS HR = 3.38; p = 0.013), NOTCH1 (OS HR 2.28, p = 0.086), and CNTRL (OS HR 2.42; p = 0.090). Conclusions This is one of the largest retrospective reports analyzing genomic aberrations in relation to clinical outcomes for patients with DDLPS. Our results suggest therapies targeting abnormalities should be explored and confirmation of prognostic markers is needed. Dedifferentiated liposarcoma is one of the most common subtypes of soft tissue sarcoma yet little is known of its molecular aberrations and possible impact on outcomes. The work presented here is an evaluation of genetic abnormalities among a population of patients with dedifferentiated liposarcoma and how they corresponded with survival and risk of metastases. There were notable gene mutations and amplifications commonly found, some of which had interesting prognostic implications.

Abstract Background The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Main Body This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. Conclusion Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field, and include new PET-labelling methods for 11C and 18F, the importance of choosing the proper chelator for a given radioactive metal ion, implications of total body PET on use of radiopharmaceuticals, legislation issues and radionuclide therapy including the emerging role of 161Tb.

Because of its low cost and suitable qualities, mineral oil (MO) has been commonly employed in transformers. Alternative liquid insulations with great characteristics have recently been presented. Natural ester (NE) and palm oil (PO) are considered alternative liquid insulations. This paper aims to study the physical and chemical properties of NE and PO which were used in a transformer for 21 months. All of the liquid insulation test specimens were sampled every 3 months. Physical properties of the liquid insulation, i.e., interfacial tension (IFT), viscosity, and particles count, were examined. Chemical properties of the liquid insulation, i.e., moisture content, acidity, corrosive sulfur, and furanic compound (2-FAL), were investigated. IFT, particles count, moisture content, acidity, and 2-FAL test results indicated deterioration of liquid insulations of the used liquid insulation; however, there is no observation change for particles amount and acidity of NE. The other test results were not found significantly change.