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Background: Metagenomic next-generation sequencing (mNGS) for pathogen detection offers the potential for broad pathogen detection directly from clinical specimens. However, the yield and impact of testing is variable, financial cost is high, and questions surrounding its optimal use remain. Our pediatric institution used a clinical committee-based approach to discuss and approve or deny mNGS test requests. In this study, we evaluate the patient characteristics for which mNGS testing was considered, test yield, and clinical impact of mNGS results when employing this model of diagnostic stewardship., Methods: Patients for which plasma cell-free DNA mNGS testing was requested and assessed by the clinical committee between August 1, 2018, and April 30, 2021, were included. The committee discussion emails were used to evaluate reasons for making the test request and treatment plans. Patient characteristics and additional clinical information were gathered by chart review. For approved cases, the clinical impact of the mNGS results were retrospectively adjudicated by infectious disease and clinical microbiology experts., Results: Twelve requests for plasma cell-free DNA mNGS were evaluated and 9 were approved. mNGS results led to a positive clinical management change in 55% of approved requests. Negative clinical impact of mNGS testing did not occur during the study. The patients for which testing requests were denied had resolution of symptoms without further intervention., Conclusions: This committee-based test request approval diagnostic stewardship model has the potential to support high-yield mNGS testing while using healthcare resources responsibly., (© Association for Diagnostics & Laboratory Medicine 2025. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Endometriosis, the growth of endometrial-like tissue outside the uterus, causes chronic pain and infertility in 10 % of reproductive-aged women worldwide. Unfortunately, no permanent cure exists, and current medical and surgical treatments offer only temporary relief. Endometriosis is a chronic inflammatory disease characterized by immune system dysfunction. Our previous study showed aberrant activation of signal transducer and activator of transcription 3 (STAT3) in endometriosis. Our transcriptomic analysis of uterine tissue from uterine-specific Stat3 knock-out mice identifies that STAT3 regulates inflammatory and immune-related genes. Here, we evaluate cerium-oxide nanoparticles (nanoceria) as a non-steroidal anti-inflammatory drug for endometriosis theranostics. Our in vitro studies validate the multi-enzymatic properties of nanoceria, enabling the transition of pro-inflammatory macrophages to an anti-inflammatory state in J774 macrophage cells. In vivo, treatment of endometriosis mice with nanoceria reveals its ability to passively accumulate at ectopic lesions. The nanoceria conjugated with indocyanine green are non-invasively trackable to ectopic lesions. Therefore, immune modulation and anti-inflammatory effects of nanoceria significantly reduce development of ectopic lesions while minimizing off-target effects, such as avoiding interference with pregnancy including implantation and decidualization. Our results suggest that aberrant STAT3 activation is a major contributor to endometriosis, and nanoceria offers a novel theranostic approach for endometriosis., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: This study investigated how obesity, BMI ≥ 30 kg/m 2 , abdominal adiposity, and systemic inflammation relate to neuroinflammation using diffusion basis spectrum imaging., Methods: We analyzed data from 98 cognitively normal midlife participants (mean age: 49.4 [SD 6.2] years; 34 males [34.7%]; 56 with obesity [57.1%]). Participants underwent brain and abdominal magnetic resonance imaging (MRI), blood tests, and amyloid positron emission tomography (PET) imaging. Abdominal visceral and subcutaneous adipose tissue (VAT and SAT, respectively) was segmented, and Centiloids were calculated. Diffusion basis spectrum imaging parameter maps were created using an in-house script, and tract-based spatial statistics assessed white matter differences in high versus low BMI values, VAT, SAT, insulin resistance, systemic inflammation, and Centiloids, with age and sex as covariates., Results: Obesity, high VAT, and high SAT were linked to lower axial diffusivity, reduced fiber fraction, and increased restricted fraction in white matter. Obesity was additionally associated with higher hindered fraction and lower fractional anisotropy. Also, individuals with high C-reactive protein showed lower axial diffusivity. Higher restricted fraction correlated with continuous BMI and SAT particularly in male individuals, whereas VAT effects were similar in male and female individuals., Conclusions: The findings suggest that, at midlife, obesity and abdominal fat are associated with reduced brain axonal density and increased inflammation, with visceral fat playing a significant role in both sexes., (© 2024 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Objective: To evaluate total, insulin-mediated, and non-insulin-mediated glucose disposal (TGD, IMGD, and NIMGD) after ingesting glucose in people with obesity and different glycemic status., Research Design and Methods: We developed and validated a new glucose tracer model in conjunction with an oral glucose tolerance test to determine IMGD, NIMGD, and TGD (sum of IMGD and NIMGD) after glucose ingestion in four groups of people: 1) lean with normal glucose tolerance (NGT), 2) obese with insulin resistance and NGT due to hyperinsulinemia (Ob-NGT group), 3) obese with insulin resistance and impaired glucose tolerance (IGT) due to inadequate hyperinsulinemia (Ob-IGT group), and 4) obese with insulin resistance and type 2 diabetes due to marked insulin insufficiency (Ob-T2D group). In addition, we evaluated the effect of intensive lifestyle therapy (ILT) that caused ∼15% weight loss on IMGD and NIMGD in people with obesity and type 2 diabetes (T2D)., Results: IMGD progressively decreased and NIMGD progressively increased from lean to Ob-NGT to Ob-IGT to Ob-T2D. IMGD accounted for about 70%, 65%, 50%, and 20% of TGD, and NIMGD accounted for ∼40%, 35%, 50%, and 80% of TGD in lean, Ob-NGT, Ob-IGT and Ob-T2D, respectively. Although NIMGD was approximately twofold and approximately threefold higher in Ob-IGT and Ob-T2D compared with Ob-NGT, NIMGD only partially compensated for markedly impaired IMGD in the Ob-IGT and Ob-T2D. ILT in people with obesity and T2D increased IMGD and decreased NIMGD., Conclusions: NIMGD is a major mechanism of postprandial TGD in people with insulin resistance and inadequate insulin secretion., (© 2024 by the American Diabetes Association.)

Trans-kingdom interactions between cells play pivotal roles in shaping intricate ecological and biological networks. However, our grasp of these interactions remains incomplete. Specifically, the vast phylogenetic spectrum of microorganisms capable of interacting with a given host cell type remains obscure, primarily due to the absence of efficient, high-throughput, single-cell resolution systems that can rapidly decipher these interactions. Here, we introduce μREACT (Microfluidic system for Rapid Evaluation of bacterial Adherence and Communication in Trans-kingdom interactions), a microfluidic system designed to analyze interkingdom interactions. μREACT not only unveiled both recognized and previously unknown interactions but also enabled their detailed characterization. The system features the use of microfluidic dielectrophoretic separation of bacteria that adhere to host cells at single-cell (digital) resolution, and enabled the sorting of 10 7 adherent microorganisms per hour, representing a comparable throughput to conventional flow cytometry systems, but without requiring any labeling. The analysis of soil microbial samples using μREACT revealed several bacterial species previously known to have high adherence to mammalian host cells, as well as new interactions involving strains that displayed hallmarks of emerging endosymbiosis. Taken together, μREACT serves as a formidable tool for identifying and characterizing webs of interkingdom interactions. Its implications extend beyond discovery of such interactions, where it has the potential to provide new insights into fundamental mechanisms driving ecosystem dynamics and biological processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Few studies show how dermatologic surgeons manage problems with site identification., Objective: To estimate frequency and characterize management of skin cancer treated by surgery when the anatomic location of the tumor is in question., Methods: Nationwide, prospective, multisite cohort study., Results: Among 17,076 cases at 22 centers, 98 (0.60%) were lesions in question for which site identification was initially uncertain, with these more often in patients who were male, older, and biopsied more than 30 days ago. Surgeons employed on average 5.0 (95% CI: 4.61-5.39) additional techniques to confirm the site location, with common approaches including: re-checking available documentation (90 lesions, 92%); performing an expanded physical examination (89 lesions, 91%); and asking the patient to point using a mirror (61 lesions, 62%). In 15%, photographs were requested from the biopsying provider, and also in 15%, frozen section biopsies were obtained. In 10%, the referring physician was contacted. Eventually, surgeons succeeded in definitively identifying 82% (80 of 98) of initially uncertain sites, with the remaining 18% (18 of 98) postponed. Most postponed surgeries were at non-facial sites., Limitations: Sites were academic centers., Conclusions: When the anatomic location of the tumor is uncertain, dermatologic surgeons use multiple methods to identify the site, and sometimes cases are postponed., Competing Interests: Conflicts of interest Dr Bolotin reported serving as principal investigator on a clinical trial sponsored by Replimune outside the submitted work. Dr Cohen reported serving as a clinical investigator, consultant, or speaker or trainer for Accure, Allergan, Almirall/Athenex, Avuta, Biofrontera Bioscience, Biopelle, Brickell Biotech, Croma, Elta, Endo Pharmaceuticals, Ferndale, Galderma, InMode, IntraDerm, Lutronic, Merz, Novan, PCA, Pulse Biosciences, Raziel, Recros Medica, Revance, Revision, Sciton, and Sente outside the submitted work. Dr Council reported receiving personal fees from Sanofi-Genzyme Regeneron, AbbVie, and Castle Biosciences outside the submitted work. Dr Schmults reported serving as the National Comprehensive Cancer Network nonmelanoma panel chair, on the American Society for Dermatologic Surgery board of directors, and as International Society for Dermatologic and Esthetic Surgery secretary. Dr Xu serves as the National Comprehensive Cancer Network nonmelanoma panel member. Drs Ahmed, Campbell, Ibrahim, Kang, Aylward, Bari, Cherpelis, Condon, Farhang, Firoz, Garrett, Geronemus, Golda, Humphreys, Hurst, Jiang, Karia, Asadi, Kouba, MacFarlane, Maher, Miller, Moioli, Morrow, Neckman, Pearson, Peterson, Poblete-Lopez, Prather, Ranario, Rubin, Swanson, Urban, Xu, Pearlman, Yoo, Harikumar, Schaeffer, Iyengar, Poon, Cahn and Alam and authors Shi, Koza, Ma, Haq, Nadir, Yi, Dave, Hisham, Lin, Dirr, Bhatti, Helming, Jacobson, and Weil have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: To investigate the enduring disparities in adverse COVID-19 events between urban and rural communities in the United States, focusing on the effects of SARS-CoV-2 vaccination and therapeutic advances on patient outcomes., Methods: Using National COVID Cohort Collaborative (N3C) data from 2021 to 2023, this retrospective cohort study examined COVID-19 hospitalization, inpatient death, and other adverse events. Populations were categorized into urban, urban-adjacent rural (UAR), and nonurban-adjacent rural (NAR). Adjustments included demographics, variant-dominant waves, comorbidities, region, and SARS-CoV-2 treatment and vaccination. Statistical methods included Kaplan-Meier survival estimates, multivariable logistic, and Cox regression., Findings: The study included 3,018,646 patients, with rural residents constituting 506,204. These rural dwellers were older, had more comorbidities, and were less vaccinated than their urban counterparts. Adjusted analyses revealed higher hospitalization odds in UAR and NAR (aOR 1.07 [1.05-1.08] and 1.06 [1.03-1.08]), greater inpatient death hazard (aHR 1.30 [1.26-1.35] UAR and 1.37 [1.30-1.45] NAR), and greater risk of other adverse events compared to urban dwellers. Delta increased, while Omicron decreased, inpatient adverse events relative to pre-Delta, with rural disparities persisting throughout. Treatment effectiveness and vaccination were similarly protective across all cohorts, but dexamethasone post-ventilation was effective only in urban areas. Nirmatrelvir/ritonavir and molnupiravir better protected rural residents against hospitalization., Conclusions: Despite advancements in treatment and vaccinations, disparities in adverse COVID-19 outcomes persist between urban and rural communities. The effectiveness of some therapeutic agents appears to vary based on rurality, suggesting a nuanced relationship between treatment and geographic location while highlighting the need for targeted rural health care strategies., (© 2024 The Author(s). The Journal of Rural Health published by Wiley Periodicals LLC on behalf of National Rural Health Association.)

Competing Interests: Conflict of Interest KB holds patents both domestic and foreign related to pro-dopamine regulation complexes and genetic testing for addiction risk. Through his company Synaptamine inc., licensed patents on KB220Z to Victory nutrition international, LLC., There are no other conflicts to report.

Introduction: Time-limited trial (TLT) is a structured approach between clinicians and seriously ill patients or their surrogates to discuss patients' values and preferences, prognosis, and shared decision-making to use specific therapies for a prespecified period of time in the face of prognostic uncertainty. Some evidence exists that this approach may lead to more patient-centered care in the intensive care unit; however, it has never been evaluated in the emergency department (ED). The study protocol aims to assess the feasibility and acceptability of TLTs initiated in the ED., Methods and Analysis: We will conduct a parallel group, clinician-level, pilot randomized clinical trial among 40 ED clinicians. We will measure feasibility (e.g., the time it takes to conduct the TLTs by ED clinicians) and clinician and patient-reported acceptability of the TLT, and also track patients' clinical outcomes via medical record review., Discussion: This study protocol will investigate the potential of TLT initiated in the ED to lead to patient-centered intensive care utilization. By doing so, the study intends to improve palliative care integration for seriously ill older adults in the ED and intensive care unit., Trial Identifier and Registry Name: ClinicalTrials.gov ID: NCT06378151 https://clinicaltrials.gov/study/NCT06378151; Pre-results; a randomized controlled trial: Time-limited Trials in the Emergency Department., Competing Interests: Dr. Kei Ouchi has received funding personally from Jolly Good, Inc (a virtual reality company) for consulting. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare., (Copyright: © 2024 Hashimoto 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.)

Background: Thymidine phosphorylase (TYMP) promotes platelet activation and thrombosis while suppressing vascular smooth muscle cell (VSMC) proliferation. Both processes are central to the development and progression of abdominal aortic aneurysms (AAAs). We hypothesize that TYMP plays a role in AAA development. Methods: Male wild-type (WT) C57BL/6J and Tymp -/- mice, fed a Western diet (WD) (TD.88137), were subjected to the 4-week Ang II infusion-induced AAA model. AAA progression was monitored by echography and confirmed through necropsy. Whole-body inflammation was assessed using a plasma cytokine array. Mechanistic studies were conducted using TYMP-overexpressing rat VSMC cell lines and primary VSMCs cultured from WT and Tymp -/- mouse thoracic aortas. Histological studies were performed on human AAA and normal aorta samples. Results: Elevated TYMP levels were observed in human AAA vessel walls. While WT mice exhibited a 28.6% prevalence of Ang II infusion-induced AAA formation, Tymp -/- mice were protected. TYMP enhanced MMP2 expression, secretion, and activation in VSMCs, which was inhibited by tipiracil, a selective TYMP inhibitor. Systemically, TYMP promoted proinflammatory cytokine expression, and its absence attenuated TNF- α -induced MMP2 and AKT activation. WT VSMCs treated with platelets lacking TYMP showed a higher proliferation rate than cells treated with WT platelets. Additionally, TYMP increased activated TGF β 1 expression in cultured VSMCs and human AAA vessel walls. In WT VSMCs, TYMP augmented thrombospondin-1 type 1 repeat domain (TSR)-stimulated TGF β 1 signaling, increasing connective tissue growth factor and MMP2 production. TSR also enhanced AKT activation in WT VSMCs but had the opposite effect in Tymp -/- cells. TSR-enhanced MMP2 activation in WT VSMCs was attenuated by LY294002 (a PI3K inhibitor) but not by SB431542 (a TGF β 1 inhibitor); both inhibitors had indiscernible effects on Tymp -/- VSMC. Conclusion: TYMP emerges as a novel regulatory force in vascular biology, influencing VSMC function and inflammatory responses to promote AAA development., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Liang Hong et al.)

Primary blast exposure is a predominant cause of mild traumatic brain injury (mTBI) among veterans and active-duty military personnel, and affected individuals may develop long-lasting behavioral disturbances that interfere with quality of life. Our prior research with the "Missouri Blast" model demonstrated behavioral changes relevant to deficits in cognitive and affective domains after exposure to low-intensity blast (LIB). In this study, behavioral evaluations were extended to 3 months post-LIB injury using multifaceted conventional and advanced behavioral paradigms. C57BL/6J male mice, aged 2 months old, were subjected to a non-inertial primary LIB-induced mTBI by detonating 350 g of C-4 at a 3-m distance on 1-m-tall platforms. Three months after injury, mice were evaluated using the open-field test (OFT), social interaction test, and advanced Erasmus Ladder paradigm. With OFT, no apparent anxiety-like changes were detected with the LIB-exposed mice and sham controls, and both groups displayed similar center-zone activities. Although no social interaction parameters reached significance, a majority of LIB-exposed mice initiated less than 50% of interactions compared with their interaction partners, suggesting decreased sociability. With the Erasmus Ladder test to assess motor functions, associative learning, and stimulus response, LIB-exposed mice appeared to display increased instances of leaving before the cue, reminiscent of "escape behavior," indicative of anxiety-related activity different from that OFT detected. Overall, these results revealed subtle multifaceted long-lasting anxiety-relevant effects following LIB exposure. The "Missouri Blast" platform offers a basis for future research to investigate the underlying biological mechanism(s) leading to domain-specific behavioral changes., (© The Author(s) 2024. Published by Mary Ann Liebert, Inc.)

Coxiella burnetii (Cb), the causative agent of Q fever, replicates within host macrophages by modulating immune responses through poorly understood mechanisms. Long non-coding RNAs (lncRNAs) are emerging as critical regulators of inflammation, yet their role in Cb pathogenesis remains largely unexplored. Here, we employed a global transcriptomic approach to identify lncRNAs specific to Cb infection in THP-1 derived macrophages, compared to 15 other microbial infections. CYP1B1-AS1 was uniquely regulated in a spatio-temporal manner during Cb infection. Promoter assays revealed that CYP1B1-AS1 is transcribed by AHR from a bidirectional promoter, enhancing CYP1B1 expression in cis . Inhibition of CYP1B1-AS1 and CYP1B1 increased reactive oxygen species (ROS), mitochondrial membrane depolarization, and apoptosis, suggesting their role in dampening host cell death. Additionally, immunoprecipitation followed by mass spectrometry identified the mitochondrially localized Cb effector CBU_0937 as an interactor of the CYP1B1 enzyme. These events facilitate Cb intracellular survival. Our findings identify CYP1B1-AS1 as a potential molecular target for combating Cb infection., Competing Interests: Competing interests The authors declare no other competing interests.

Background: The impact of pre-infection vaccination on the risk of long COVID remains unclear in the pediatric population. We aim to assess the effectiveness of BNT162b2 on long COVID risks with various strains of the SARS-CoV-2 virus in children and adolescents, using comparative effectiveness methods. We further explore if such pre-infection vaccination can mitigate the risk of long COVID beyond its established protective benefits against SARS-CoV-2 infection using causal mediation analysis., Methods: We conducted real-world vaccine effectiveness study and mediation analysis using data from twenty health systems in the RECOVER PCORnet electronic health record (EHR) Program. Three independent cohorts were constructed including adolescents (12-20 years) during the Delta phase (July 1-November 30, 2021), children (5-11 years) and adolescents (12-20 years) during the Omicron phase (January 1-November 30, 2022). The intervention is first dose of the BNT162b2 vaccine in comparison with no receipt of COVID-19 vaccine. The outcomes of interest include conclusive or probable diagnosis of long COVID following a documented SARS-CoV-2 infection, and body-system-specific condition clusters of post-acute sequelae of SARS-CoV-2 infection (PASC), such as cardiac, gastrointestinal, musculoskeletal, respiratory, and syndromic categories. The effectiveness was reported as (1-relative risk)∗100 and mediating effects were reported as relative risks., Findings: 112,590 adolescents (88,811 vaccinated) were included in the cohort for the analysis against Delta variant, and 188,894 children (101,277 vaccinated), and 84,735 adolescents (37,724 vaccinated) were included for the analysis against Omicron variant. During the Delta period, the estimated effectiveness of the BNT162b2 vaccine against long COVID among adolescents was 95.4% (95% CI: 90.9%-97.7%). During the Omicron phase, the estimated effectiveness against long COVID among children was 60.2% (95% CI: 40.3%-73.5%) and 75.1% (95% CI: 50.4%-87.5%) among adolescents. The direct effect of vaccination, defined as the effect beyond their impact on SARS-CoV-2 infections, was found to be statistically non-significant in all three study cohorts, with estimated relative risk of 1.08 (95% CI: 0.75-1.55) in the Delta study among adolescents, 1.24 (95% CI: 0.92-1.66) among children and 0.91 (95% CI: 0.69-1.19) among adolescents in the Omicron studies. Meanwhile, the estimated indirect effects, which are effects through protecting SARS-CoV-2 infections, were estimated as 0.04 (95% CI: 0.03-0.05) among adolescents during Delta phase, 0.31 (95% CI: 0.23-0.42) among children and 0.21 (95% CI: 0.16-0.27) among adolescents during the Omicron period., Interpretation: Our study suggests that BNT162b2 was effective in reducing risk of long COVID outcomes in children and adolescents during the Delta and Omicron periods. The mediation analysis indicates the vaccine's effectiveness is primarily derived from its role in reducing the risk of SARS-CoV-2 infection., Funding: National Institutes of Health., Competing Interests: Dr. Mosa is a board member of i2b2tranSMART Foundation. Dr. Jhaveri is a consultant for Gilead, AstraZeneca, Sanofi, and Seqiru; receives grants from GSK, CDC, and AHRQ; holds an editorial stipend Editor-in-Chief of the Journal of the Pediatric Infectious Diseases Society (JPIDS); and receives royalties from UpToDate., (© 2024 The Authors.)

Disruption of HIV-1 Integrase (IN) interactions with the host-factor Lens Epithelium-Derived Growth Factor (LEDGF)/p75 leads to decreased, random integration, increased latent infection, and described here, accumulation of HIV-1 antisense RNA (asRNA). asRNA increase was observed following interruptions of IN-LEDGF/p75 interactions either through pharmacologic perturbations of IN-LEDGF/p75 by treatment with allosteric HIV-1 integrase inhibitors (ALLINIs) or in cell lines with LEDGF genetic knockout. Additionally, by impairing Tat-dependent HIV transcription, asRNA abundance markedly increases. Illumina sequencing characterization of asRNA transcripts in primary T cells infected in the presence of ALLINIs showed that most initiate from within the HIV-1. Overall, loss of IN-LEDGF/p75 interactions increase asRNA abundance. Understanding the relationship between ALLINIs, integration sites, asRNA, and latency could aid in future therapeutic strategies., Competing Interests: Competing interests: Authors declare that they have no competing interests.

Type 1 diabetes (T1D) develops spontaneously despite functional antigen presentation machinery in the thymus and a perceptible central tolerance process. We found that intrathymic enrichment with IL-4 fine tunes signaling through the IL-4/IL-13 heteroreceptor (HR) in early thymic progenitors (ETPs), augments negative selection of self-reactive T cells, sustains a diverse T cell repertoire devoid of clones expressing disease-associated T cell receptor (TCR) genes, and protects the nonobese diabetic (NOD) mouse from T1D. Indeed, optimal IL-4 activates STAT transcription factors to program ETP fate decision toward CD11c+CD8α+ dendritic cells (DCs) agile in negative T cell selection and clonal deletion of diabetogenic T cells. However, due to diminished invariant natural killer T (iNKT) 2 cell frequency in the NOD thymus, IL-4 is as suboptimal level, metering STAT activation to program ETP fate decision toward the T cell lineage leading to diminished negative selection, a clonally restricted TCR repertoire, and manifestation of spontaneous T1D. These insights uncover yet another interplay by which IL-4 affects T1D.

Competing Interests: Competing interests: IRM reports the following disclosures: Arthrex: paid consultant. Bone and Joint Research: editorial or governing board. Journal of Bone and Joint Surgery British: editorial or governing board. Stryker: paid consultant. AG reports the following disclosures: American Orthopaedic Society for Sports Medicine: board or committee member. Arthroscopy: editorial or governing board, Infographics Editor. Ossur: paid presenter or speaker. Smith & Nephew: paid consultant; paid presenter or speaker. JC reports the following disclosures: American Orthopaedic Society for Sports Medicine: board or committee member. Arthrex: paid consultant. Arthroscopy Association of North America: board or committee member. CONMED Linvatec: paid consultant. International Society of Arthroscopy, Knee Surgery, and Orthopaedic Sports Medicine: board or committee member. Ossur: paid consultant. Smith & Nephew: paid consultant. GM reports the following disclosures: Smith & Nephew: paid consultant. IBSA: paid consultant. International Society of Arthroscopy, Knee Surgery, and Orthopaedic Sports Medicine: board or committee member. Arthroscopy: editorial board. JBJS: editorial Board. RFL reports the following disclosures: American Journal of Sports Medicine: editorial or governing board. American Orthopaedic Society for Sports Medicine: board or committee member. Arthrex: IP royalties. International Society of Arthroscopy, Knee Surgery, and Orthopaedic Sports Medicine: board or committee member. Journal of Experimental Orthopaedics: editorial or governing board. Knee Surgery, Sports Traumatology, Arthroscopy: editorial or governing board. Ossur: IP royalties; paid consultant; research support. Smith & Nephew: IP royalties; paid consultant; research support. Journal of Knee Surgery: editorial or governing board. Orthopaedic techniques in Sports Medicine: editorial or governing board. JJI reports the following disclosures: receives funding as PI from Department of Defense Congressionally Directed Medical Research Programme Peer-Reviewed Orthopaedic Research Programme for the Surgical Timing and Rehabilitation (STaR) Trial for Multiple Ligament Knee Injuries (MLKIs): A Multicenter Integrated Clinical Trial (W81XWH-17-2-0073) and serves as President, Board of Directors for Movement Science Media/Journal of Orthopaedic and Sports Physical Therapy. GM reports the following disclosures: Smith & Nephew, IBSA: Consultant. ISAKOS: committee memberJBJS and arthroscopy: Editorial. BoardSmith & Nephew: fellowship funding. GFH III reports the following disclosures: Arthrex: consultant. MS reports the following disclosures: Arthrex: consultant and Royalties Stryker, USA Hockey Foundation: Research Funding. MEK reports the following disclosures: AANA: Research committee. AOSSM: Enduring Education committee Arthrex, Smith and Nephew: education funds. PM reports the following disclosures: Arthrex and Conmed: Consultant Arthrex, Conmed, Zimmer Biomet, Smith and Nephew, Ossur: research and fellowship support. KC reports the following disclosures: BJSM: Senior advisor. BL reports the following disclosures: Arthrex: Consultant and Royalties. JKS and KSSTA: editorial board. MM reports the following disclosures: Smith and Nephew: paid speaker. KT reports the following disclosure: deputy editor: BJSM. TGM reports the following disclosures: Arthrex: Speaker, Consultant. CORR: editorial board. EV reports the following disclosures: associate editor: BJSM Editor-in-Chief: BMJ Open SEM. AJK reports the following disclosures: Arthrex: Consultant, IP royalties, JRF Orthopaedics, Vericel, Responsive Arthroscopy: Consulting fees. DJO: Grants Musculoskeletal Transplant Foundation: Board of Trustees. RCS reports the following disclosures: Arthrex: education editorial board: AJSM and JBJSJPS reports the following disclosures: Thieme: Publishing Royalties DePuy: consulting fees/teaching courses Arthrex: consulting fees/teaching courses AO NA: research support, teaching and travel support. AO Foundation—teaching/travel support. Journal of Knee Surgery—Editor-In-Chief. CE reports the following disclosures: Canadian Institutes of Health Research, Canada Foundation for Innovation, Canada Research Chairs Programme and National Football League Play Smart Play Safe Programme: peer-reviewed research support. Associate Editor: BJSM. External Advisory Board: HitIQ Chairperson: Sport injury Prevention Research Centre, an IOC Research Centre for Prevention of Injury and Protection of Athlete Health. HG reports the following disclosures: associate editor: BJSM, JOSPT. RGM reports the following disclosures: mend nutrition. Royalties from Springer and Demos for books. JLC reports the following disclosures: AANA: research support. AO trauma: research support. Arthrex: IP royalties; paid consultant; research support. Bioventus: paid consultant. Boehringer Ingelheim: paid consultant. Collagen Matrix: paid consultant; research support. GE healthcare: research support Journal of Knee Surgery: editorial or governing board. Midwest Transplant Network: board or committee member. Musculoskeletal Transplant Foundation: board or committee member; IP royalties; research support. National Institutes of Health (NIAMS & NICHD): research support. OREF: research support. Orthopaedic Trauma Association: research support. PCORI: research support. Regenosine: research support. SITES Medical: research support Thieme: publishing royalties, financial or material support. Trupanion: paid consultant. VM reports the following disclosures: Smith & Nephew, Newclip: Consultant Ostesys: Shareholder Arthrex, Smith & Nephew: educational grants. ISAKOS: board or committee member. KSSTA: Deputy Editor-In-Chief. MTH reports the following disclosures: Knee Surgery Sports Traumatology Arthroscopy (KSSTA): Deputy Editor-In-Chief. APKASS journal, MLT journal, Arthroskopie, Das Knie (DKG), board or committee member. European Knee Associates (EKA): Past Chairman. ESSKA Milan 2020 and 2021: Scientific Chairman. ISAKOS: Arthroplasty Committee, ESSKA: Cartilage Committee. German Knee Society: board or committee member. Personalized Arthroplasty Society (PAS): 2nd vice president DepuySynthes, Smith & Nephew, Symbios, Medacta: Consultant DepuySynthes, Finceramica, Symbios, Mathys, Arthrex, SIWF, Deutsche Arthrose-Hilfe, Bangerter-Rhyner-Stiftung: research grants. NM, HP, SPE, KDS, CJW, FRN, MT, DCJvR, EK, DBW, MDM, GCF, CH, LE, RS and NP report no competing interests.

Multiligament knee injuries (MLKIs) represent a broad spectrum of pathology with potentially devastating consequences. Currently, disagreement in the terminology, diagnosis and treatment of these injuries limits clinical care and research. This study aimed to develop consensus on the nomenclature, diagnosis, treatment and rehabilitation strategies for patients with MLKI, while identifying important research priorities for further study. An international consensus process was conducted using validated Delphi methodology in line with British Journal of Sports Medicine guidelines. A multidisciplinary panel of 39 members from 14 countries, completed 3 rounds of online surveys exploring aspects of nomenclature, diagnosis, treatment, rehabilitation and future research priorities. Levels of agreement (LoA) with each statement were rated anonymously on a 5-point Likert scale, with experts encouraged to suggest modifications or additional statements. LoA for consensus in the final round were defined 'a priori' if >75% of respondents agreed and fewer than 10% disagreed, and dissenting viewpoints were recorded and discussed. After three Delphi rounds, 50 items (92.6%) reached consensus. Key statements that reached consensus within nomenclature included a clear definition for MLKI (LoA 97.4%) and the need for an updated MLKI classification system that classifies injury mechanism, extent of non-ligamentous structures injured and the presence or absence of dislocation. Within diagnosis, consensus was reached that there should be a low threshold for assessment with CT angiography for MLKI within a high-energy context and for certain injury patterns including bicruciate and PLC injuries (LoA 89.7%). The value of stress radiography or intraoperative fluoroscopy also reached consensus (LoA 89.7%). Within treatment, it was generally agreed that existing literature generally favours operative management of MLKI, particularly for young patients (LoA 100%), and that single-stage surgery should be performed whenever possible (LoA 92.3%). This consensus statement will facilitate clinical communication in MLKI, the care of these patients and future research within MLKI., Competing Interests: ompeting interests: IRM reports the following disclosures: Arthrex: paid consultant; Bone and Joint Research: editorial or governing board; Journal of Bone and Joint Surgery—British: editorial or governing board; Stryker: paid consultant. AG reports the following disclosures: American Orthopaedic Society for Sports Medicine: board or committee member; Arthroscopy: editorial or governing board, Infographics Editor; Ossur: paid presenter or speaker; Smith & Nephew: paid consultant; paid presenter or speaker. JC reports the following disclosures: American Orthopaedic Society for Sports Medicine: board or committee member; Arthrex: paid consultant; Arthroscopy Association of North America: board or committee member; Conmed Linvatec: paid consultant; International Society of Arthroscopy, Knee Surgery, and Orthopaedic Sports Medicine: board or committee member; Ossur: paid consultant; Smith & Nephew: paid consultant. GM reports the following disclosures: Smith & Nephew: paid consultant; IBSA: paid consultant; International Society of Arthroscopy, Knee Surgery, and Orthopaedic Sports Medicine: board or committee member; Arthroscopy: editorial board; JBJS: editorial board. RFLP reports the following disclosures: American Journal of Sports Medicine: editorial or governing board; American Orthopaedic Society for Sports Medicine: board or committee member; Arthrex: IP royalties; International Society of Arthroscopy, Knee Surgery, and Orthopaedic Sports Medicine: board or committee member; Journal of Experimental Orthopaedics: editorial or governing board; Knee Surgery, Sports Traumatology, Arthroscopy: editorial or governing board; Ossur: IP royalties, paid consultant, research support; Smith & Nephew: IP royalties, paid consultant; research support; Journal of Knee Surgery: editorial or governing board; Orthopaedic Techniques in Sports Medicine: editorial or governing board. JJI reports the following disclosures: receives funding as PI from Department of Defense Congressionally Directed Medical Research Programme Peer Reviewed Orthopaedic Research Programme for the Surgical Timing and Rehabilitation (STaR) Trial for Multiple Ligament Knee Injuries (MLKIs): A Multicenter Integrated Clinical Trial (W81XWH-17-2-0073) and serves as President, Board of Directors for Movement Science Media/Journal of Orthopaedic and Sports Physical Therapy. GM reports the following disclosures: Smith & Nephew, IBSA: consultant; ISAKOS: committee member; JBJS and arthroscopy: editorial board; Smith & Nephew: fellowship funding. GFH III reports the following disclosures: Arthrex: consultant. MS reports the following disclosures: Arthrex: consultant and royalties; Stryker, USA Hockey Foundation: research funding; MEK reports the following disclosures: AANA: research committee; AOSSM: enduring education committee; Arthrex; Smith & Nephew: education funds; PMacD reports the following disclosures: Arthrex and Conmed: consultant; Arthrex, Conmed, Zimmer Biomet, Smith & Nephew, Ossur: research and fellowship support; KMC reports the following disclosures: BJSM: senior advisor. BL reports the following disclosures: Arthrex: consultant and royalties; JKS and KSSTA: editorial board; MJM reports the following disclosures: Smith & Nephew: paid speaker. KT reports the following disclosure: Deputy Editor: BJSM. TGM reports the following disclosures: Arthrex: speaker, consultant; CORR: editorial board. EV reports the following disclosures: Associate Editor: BJSM; Editor-in-Chief: BMJ Open SEM. AJK reports the following disclosures: Arthrex: consultant, IP royalties; JRF Orthopaedics, Vericel, Responsive Arthroscopy: consulting fees; DJO: grants; Musculoskeletal Transplant Foundation: board of trustees. RCS reports the following disclosures: Arthrex: education; Editorial Board: AJSM and JBJS. JPS reports the following disclosures: Thieme: Publishing Royalties; DePuy: consulting fees/teaching courses; Arthrex: consulting fees/teaching courses; AO NA: research support, teaching and travel support; AO Foundation: teaching/travel support; Journal of Knee Surgery: Editor-in-Chief. CE reports the following disclosures: Canadian Institutes of Health Research, Canada Foundation for Innovation, Canada Research Chairs Programme and National Football League Play Smart Play Safe Programme: peer-reviewed research support; Associate Editor: BJSM; External Advisory Board: HitIQ Chairperson: Sport Injury Prevention Research Centre, an IOC Research Centre for Prevention of Injury and Protection of Athlete Health. HG reports the following disclosures: Associate Editor: BJSM, JOSPT. RGM reports the following disclosures: Mend nutrition. Royalties from Springer and Demos for books. JLC reports the following disclosures: AANA: research support; AO Trauma: research support; Arthrex: IP royalties; paid consultant; research support; Bioventus: paid consultant; Boehringer Ingelheim: paid consultant; Collagen Matrix: paid consultant; research support; GE Healthcare: research support; Journal of Knee Surgery: editorial or governing board; Midwest Transplant Network: board or committee member; Musculoskeletal Transplant Foundation: board or committee member; IP royalties; research support; National Institutes of Health (NIAMS & NICHD): research support; OREF: research support; Orthopaedic Trauma Association: research support; PCORI: research support; Regenosine: research support; SITES Medical: research support; Thieme: publishing royalties, financial or material support; Trupanion: paid consultant. VM reports the following disclosures: Smith & Nephew, Newclip: consultant; Ostesys: Shareholder; Arthrex, Smith & Nephew: educational grants; ISAKOS: board or committee member; KSSTA: Deputy Editor-in-Chief. MTH reports the following disclosures: Knee Surgery Sports Traumatology Arthroscopy (KSSTA): Deputy Editor-in-Chief; APKASS journal, MLT journal, Arthroskopie, Das Knie (DKG): board or committee member; European Knee Associates (EKA): Past Chairman; ESSKA Milan 2020 and 2021: Scientific Chairman; ISAKOS: Arthroplasty Committee; ESSKA: Cartilage Committee; German Knee Society: board or committee member; Personalized Arthroplasty Society (PAS): 2nd vice president DepuySynthes, Smith & Nephew, Symbios, Medacta: cconsultant; DepuySynthes, Finceramica, Symbios, Mathys, Arthrex, SIWF, Deutsche Arthrose-Hilfe, Bangerter-Rhyner-Stiftung: research grants. NM, HP, SPE, KDS, CJW, FRN, MT, DCCJvR, EK, DBW, MDM, GCF, CH, LE, RS and NP report no competing interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Clear cell renal cell carcinoma is the most common form of kidney cancer, accounting for 75% of malignant kidney tumors, and is generally associated with poor patient outcomes. With risk factors including smoking, obesity, and hypertension, all of which have a high prevalence in the United States and Europe, as well as genetic factors including tuberous sclerosis complex and Von Hippel-Lindau syndrome, there is an increasing need to expand our present understanding. The current clear cell renal cell carcinoma knowledge is outdated, with obsolete diagnostic criteria and moderately invasive surgical treatments still prevailing, partially ascribed to its resistance to chemotherapy and radiation therapy. The standard of treatment relies on surgical intervention, including radical nephrectomy and partial nephrectomy, while more recent treatments target neoplastic growth pathways and immune regulation checkpoints.

Gallstone disease has plagued humanity since antiquity. Its recognition and treatment has been refined through decades as surgical technique and imaging capabilities have advanced. With the rise of the obesity epidemic and metabolic syndrome, its prevalence is also increasing. This review provides an overview of the various manifestations of gallstone disease and treatment modalities appropriate for its resolution., Competing Interests: Disclosure The authors have no disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

AMP-activated protein kinase (AMPK) plays a crucial role in governing essential cellular functions such as growth, proliferation, and survival. Previously, we observed increased vulnerability to bacterial (Staphylococcus aureus) endophthalmitis in global AMPKα1 knockout mice. In this study, we investigated the specific involvement of AMPKα1 in myeloid cells using LysMCre;AMPKα1fl mice. Our findings revealed that whereas endophthalmitis resolved in wild-type C57BL/6 mice, the severity of the disease progressively worsened in AMPKα1-deficient mice over time. Moreover, the intraocular bacterial load and inflammatory mediators (e.g., IL-1β, TNF-α, IL-6, and CXCL2) were markedly elevated in the LysMCre;AMPKα1fl mice. Mechanistically, the deletion of AMPKα1 in myeloid cells skewed macrophage polarization toward the inflammatory M1 phenotype and impaired the phagocytic clearance of S. aureus by macrophages. Notably, transferring AMPK-competent bone marrow from wild-type mice to AMPKα1 knockout mice preserved retinal function and mitigated the severity of endophthalmitis. Overall, our study underscores the role of myeloid-specific AMPKα1 in promoting the resolution of inflammation in the eye during bacterial infection. Hence, therapeutic strategies aimed at restoring or enhancing AMPKα1 activity could improve visual outcomes in endophthalmitis and other ocular infections., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Background: Osteochondral allograft transplantation (OCAT) can be performed without the need for blood-type matching or anti-rejection medications. However, other donor-recipient mismatch variables could influence outcomes. Therefore, it is critical to examine the impacts of sex and age mismatching on functional OCA survival., Methods: Prospectively collected data for patients undergoing primary knee OCAT enrolled in a lifelong outcomes registry were analyzed for functional OCA survival based on sex- and age-matched and -mismatched cohorts. Treatment failure was defined as the need for OCAT revision surgery or knee arthroplasty., Results: 162 donor-recipient pairs were analyzed; 57 (35.2%) were sex-mismatched and 89 (54.9%) were age-mismatched. Sex-mismatched OCATs were not associated with a significantly different cumulative graft survival rate when compared to sex-matched OCATs (78.9% vs 75.2% p = 0.324). Age-mismatched OCATs were not associated with a significantly different cumulative graft survival rate when compared to age-matched OCATs (71.6% vs 81.5% p = 0.398). When adjusting for sex, BMI, concomitant procedures, and surgery type, age-mismatched and sex-mismatched OCATs were not significantly associated with higher likelihood for treatment failure., Conclusion: By analyzing functional graft survival rates for donor-recipient sex- or age-mismatched OCAs following primary OCAT, the results of the present study support current donor-recipient matching protocols for OCA transplantation in the knee. Based on current evidence, donor-recipient blood-type, sex-, and age-matching are not required for safe and effective primary OCAT in the knee. However, further studies are imperative for defining modifiable variables that further optimize safety and outcomes while maximizing donor tissue quality, availability, access, and use., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: James P Stannard is a paid consultant and receives research support from Arthrex, Inc; is a paid consultant for DePuy, A Johnson & Johnson Company; is on the editorial or governing board for the Journal of Knee Surgery; receives research support from National Institutes of Health (NIAMS & NICHD); is a paid consultant for Orthopedic Designs North America; is a paid consultant for Smith & Nephew; receives publishing royalties, financial or material support from Thieme; and receives research support from the U.S. Department of Defense. Aaron Stoker receives IP royalties from Musculoskeletal Transplant Foundation. Clayton William Nuelle is a board or committee member for AAOS; is a board or committee member for the American Orthopaedic Society for Sports Medicine; receives other financial or material support from AO Foundation; is a paid presenter or speaker for Arthrex, Inc; is on the editorial or governing board, receives publishing royalties, financial or material support from Arthroscopy; is a board or committee member for Arthroscopy Association of North America; is a paid consultant for Guidepoint Consulting; and is a paid presenter or speaker for Vericel, Inc. James L Cook receives research support from AANA; receives research support from AO Trauma; receives IP royalties, is a paid consultant and receives research support from Arthrex, Inc; is a paid consultant for Bioventus; is a paid consultant for Boehringer Ingelheim; is a paid consultant and receives research support from Collagen Matrix Inc; receives research support from GE Healthcare; is on the editorial or governing board for the Journal of Knee Surgery; is a board or committee member for Midwest Transplant Network; is a board or committee member, receives IP royalties and research support from Musculoskeletal Transplant Foundation; receives research support from the National Institutes of Health (NIAMS & NICHD); receives research support from OREF; receives research support from Orthopaedic Trauma Association; receives research support from PCORI; receives research support from Regenosine; receives research support from SITES Medical; receives publishing royalties, financial or material support from Thieme; is a paid consultant for Trupanion; and receives research support from U.S. Department of Defense., (Copyright © 2024 Elsevier B.V. All rights reserved.)

With mental health needs consistently increasing in our communities and medical centers, we want to ensure that institutions are aware of the benefit and value that psychologists bring to their system and provide several pathways for consideration and structure to understand how to support the salaries and careers of psychologists working within AHCs. Leadership and administration within Academic Health Centers (AHC) often do not understand the value and measurement of productivity for psychologists being added to the medical teams. The current article aims to present varied structural models and demonstrate how productivity is reviewed for psychologists across different institutions and departments. The authors will outline the many roles that psychologists serve within academic health centers as well as the value those roles bring to the system. The overarching goal is to provide an educational article that serves as a tool for recruitment of psychologists that leaders and faculty can refer to when approaching administration in AHCs to understand the systems and roles of psychologists within medical settings. This information can be utilized to help create new positions for psychologists, aid in recruitment efforts and provide transparency for faculty currently working within AHCs who may not be aware of the varied opportunities., Competing Interests: Declarations Conflict of interest No conflicts of interest to disclose. Ethical Approval Not applicable. Consent for Publication Not applicable., (© 2024. The Author(s).)

Background: Ectodermal dysplasias (EDs) are a heterogeneous group of genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. There are currently 49 recognized EDs with molecularly confirmed etiology. The EDs are very rare disorders, individually and in aggregate. Very little is published regarding the prevalence of these rare disorders. As a result of the genomics revolution, rare diseases have emerged as a global health priority. The various disabilities arising from rare disorders, as well as diagnostic and treatment uncertainty, have been demonstrated to have detrimental effects on the health, psychosocial, and economic aspects of families affected by rare disorders. Contemporary research methodologies and databases can address what have been historic challenges encountered when conducting research on rare diseases., Objective: In this study, we aim to ascertain period prevalence rates for several of the more common ectodermal dysplasia syndromes, by querying a large multicenter database of electronic health records, Oracle Real-World Data., Methods: For each of the included ectodermal dysplasia syndromes a clinical definition was developed by a committee of international experts with interests in EDs. The clinical definitions were based upon a combination of clinical features and designated by ICD-9 and ICD-10 codes. The January 2023 version of the Oracle Real-World Data database was queried for medical records that coincided with the clinical definitions. For our study, there were 64,523,460 individual medical records queried., Results: Period prevalence rates were calculated for the following ED disorders: hypohidrotic ectodermal dysplasia, found to be 2.99 per 100,000; ectodermal dysplasia and immunodeficiency 1, 0.23 per 100,000; Clouston syndrome, 0.15 per 100,000; ectrodactyly ectodermal dysplasia and cleft lip/palate syndrome, 0.61 per 100,000; ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, 0.36 per 100,000; focal dermal hypoplasia, 0.10 per 100,000; and incontinentia pigmenti, 0.88 per 100,000., Conclusion: This study established estimated period prevalence rates for several of the ectodermal dysplasia syndromes, and it demonstrated the feasibility of utilizing large multicenter databases of electronic health records, such as Oracle Real World Data., (© 2024 Wiley Periodicals LLC.)

Multiple injurious stimuli to the brain's endothelium results in brain endothelial cell activation and dysfunction (BECact/dys) with upregulation of inflammatory signaling cascades and a decrease in bioavailable nitric oxide respectively. These injurious stimuli initiate a brain injury and a response to injury wound healing genetically programed cascade of events, which result in cellular remodeling of the neurovascular unit and blood-brain barrier with increased inflammation and permeability. These remodeling changes also include the perivascular spaces that become dilated to form enlarged perivascular spaces (EPVS) that may be identified noninvasively by magnetic resonance imaging. These EPVS are associated with and considered to be a biomarker for cerebral small vessel disease (SVD) and a dysfunctional glymphatic system with impaired removal of neurotoxic waste, which ultimately results in neurodegeneration with impaired cognition and dementia. The penultimate section discusses the understudied role of venous cerebral circulation in relation to EPVS, SVD, and the vascular contribution to cognitive impairment (VCID). The focus of this review will be primarily on BEC act/dys that associates with and contributes to the development of EPVS, SVD, and impaired glymphatic system efflux. Importantly, BEC act/dys may be a key piece of the puzzle to unlock this complicated story of EPVS and SVD. Multiple transmission electron micrographs and illustrations will be utilized to depict anatomical ultrastructure and allow for the discussion of multiple functional molecular cascades., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Immunotherapy offers a novel and promising option in the treatment of late-stage melanoma. By utilizing the immune system to assist in tumor destruction, patients have additional options after tumor progression. Immune checkpoint inhibitors reduce the ability for tumors to evade the immune system by inhibiting key surface proteins used to inactivate T-cells. Without these surface proteins, T-cells can induce cytotoxic responses against tumors. Tumor infiltrating lymphocyte therapy is a form of adoptive cell therapy that takes advantage of a small subset of T-cells that recognize and infiltrate tumors. Isolation and rapid expansion of these colonies assist the immune system in mounting a charged response that can induce remission. Tumor vaccines deliver a high dose of unique antigens expressed by tumor cells to the entire body. The introduction of large quantities of tumor antigens upregulates antigen presenting cells and leads to effective activation of the immune system against tumors. Cytokine therapy introduces high amounts of chemical messengers that are endogenous to the immune system and support T-cell expansion. While other methods of immunotherapy exist, immune checkpoint inhibitors, tumor infiltrating lymphocytes, tumor vaccines, and cytokine therapy are commonly used to treat melanoma. Like many other cancer treatments, immunotherapy is not without adverse effects, as toxicities represent a major obstacle. However, immunotherapy has been efficacious in the treatment of melanoma.

Background Artificial intelligence (AI) is a hot topic in the world of medicine. AI may be useful in identifying and sizing polyps, which influence surveillance intervals. Therefore, we examined polyp size estimation by AI using a survey study. Methods A survey study was performed using a phantom colon model. Eleven videos were produced in the colon phantom using a colonoscope. Gastroenterologists were compared to a new AI system (Argus) for sizing polyps and their impact on surveillance intervals. Results Eleven gastroenterologists completed the survey with a mean age of 51.1 ± 8.1 years and an average of 19.3 ± 10 years of experience. Mean accuracy rates for gastroenterologists were 76% ± 0.1% (range 54-89%) compared to 96% ± 0.05% for Argus. Endoscopists estimated polyp size within ± 1 mm 44 times (36%) versus 9 times (82%) with Argus. Endoscopists' surveillance recommendations were significantly more often inappropriate compared to Argus (34 vs 0). The interval of next colonoscopy was too short for 27 endoscopists (22%) and too long for seven endoscopists (6%). Conclusions AI appears to be more accurate in estimating polyp size than experienced endoscopists. Given the potential impact on surveillance intervals, AI may result in cost savings., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Institutional Review Board at the University of Missouri issued approval project #2062726. 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: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. 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, Yousaf et al.)

Hippocampal dentate gyral dysplasia is well-described in temporal lobe epilepsy and may be a risk factor for sudden, unexpected death in several populations: infants (sudden infant death syndrome [SIDS], sudden unexpected infant death [SUID]), toddlers (sudden unexpected death of a child [SUDC]), and epileptics (sudden unexpected death in epilepsy [SUDEP]). We examined reports and histopathological slides from autopsies performed at our institution from 2008 through 2016 to determine whether the presence or absence of any of the described forms of such dysplasias (duplications, hyperconvolutions, and granule cell dispersion, including bilamination), correlated with the causes of death. From well over 4000 autopsies, we identified 949 autopsies with a neuropathology examination by a neuropathologist. Of these, 205 cases (21.6%) had 1 or more of the described abnormalities of 1 or both dentate gyri; 87 (42.4%) of the individuals in this group of 205 autopsies had died suddenly and unexpectedly, including 29/90 (32.2%) cases of SUDEP, 17/31 (54.8%) cases of SUDC, and 51/104 (49.0%) cases of infants with SIDS or SUID. We conclude that these changes are readily recognizable by experienced neuropathologists and that because they are overrepresented in an autopsy population that died suddenly and unexpectedly, they may represent a risk factor for such outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Pancreatic ductal adenocarcinoma (PDAC) has proven to be a formidable cancer primarily due to its tumor microenvironment (TME). This highly desmoplastic, hypoxic, and pro-inflammatory environment has not only been shown to facilitate the growth and metastasis of PDAC but has also displayed powerful immunosuppressive capabilities. A critical cell involved in the development of the PDAC TME is the fibroblast, specifically the antigen-presenting cancer-associated fibroblast (apCAF). The pro-inflammatory environment of PDAC induces the proliferation of apCAFs, promoting immunosuppression through immune cell inactivation, immune response regulation, and expression of CD74. In conjunction with apCAFs and tumor cells, CD74 serves as a versatile promoter of PDAC by preventing tumor antigen-expression on tumor cells, upregulating the expression of immunosuppressive chemical mediators, and activating proliferative pathways to induce PDAC malignancy. This review will highlight critical mediators and pathways that promote the PDAC stroma and TME with its hypoxic and immunosuppressive properties. Further, we will highlight the nature of apCAFs and CD74, their specific roles in the PDAC TME, and their potential as targets for immunotherapy., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: By creating a review paper, there is no novel research, only research collected from prior sources that have been approved through the peer review process. Informed consent: Review paper, consent is not applicable. No data has been collected needing informed consent., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)