Instrumental variable and colocalization analyses identify endotrophin and HTRA1 as potential therapeutic targets for coronary artery disease.

Coronary artery disease (CAD) remains a leading cause of disease burden globally, and there is a persistent need for new therapeutic targets. Instrumental variable (IV) and genetic colocalization analyses can help identify novel therapeutic targets for human disease by nominating causal genes in genome-wide association study (GWAS) loci. We conducted cis-IV analyses for 20,125 genes and 1,746 plasma proteins with CAD using molecular trait quantitative trait loci variant (QTLs) data from three different studies. 19 proteins and 119 genes were significantly associated with CAD risk by IV analyses and demonstrated evidence of genetic colocalization. Notably, our analyses validated well-established targets such as PCSK9 and ANGPTL4 while also identifying HTRA1 and endotrophin (a cleavage product of COL6A3) as proteins whose levels are causally associated with CAD risk. Further experimental studies are needed to confirm the causal role of the genes and proteins identified through our multiomic cis-IV analyses on human disease.

Can Next Generation Ecological Risk Assessment Decisions Be Made Today?-A Case Study of Regulatory Risk Assessment in the United States.

We examined the need for new in vivo avian toxicity testing for three common industrial chemicals (1,2 dichloropropane, 1,1,2-trichloroethane and triphenyl phosphate) based on estimated avian exposures using fugacity and multimedia fate models for current conditions of use compared to hazard information including existing in vivo test data for the chemicals and analogs, interspecies correlation estimates and results from hundreds of acute avian dietary toxicity studies. The data indicated that acute avian toxicity is not likely to be observed below 10 ppm in the diet for any chemical with the exception of those with a specific mode of toxic action. Modeling indicated low exposure potential for terrestrial birds to any of the three chemicals, with estimated dietary concentration of less than 0.001 ppm. Despite uncertainty associated with the underlying data sources, the four order of magnitude gap between potential exposure and a minimum hazard threshold suggests that additional avian in vivo testing would not generate valuable data. However, a weight of evidence approach for integrating data is necessary to engender greater confidence among government decision-makers in cases where data from a particular in vivo study is not expected to improve risk decision-making and an existing data gap can remain unfilled.

Procedural Volume and Outcomes with Atrial Fibrillation Ablation: A Report from the NCDR AFib Ablation Registry.

BACKGROUND: The association between hospital and physician procedure volume outcome has not been well evaluated for atrial fibrillation (AF) ablation in contemporary practice. OBJECTIVE: To determine the association between hospital and physician AF ablation volume and procedural success (isolation of all pulmonary veins) and major adverse events (MAE). METHODS: Procedures reported to the NCDR AFib Ablation Registry between July 2019 and June 2022 were included. Hospital and physician procedural volumes were annualized and stratified into quartiles (Q) to compare outcomes. Three level hierarchical (patient, hospital and physician) models were used to assess the procedural volume outcome relationship. RESULTS: A total of 70,296 first-time AF ablations at 186 U.S. hospitals were included. Overall, procedural success and MAE rate were 98.5 % and 1.0% respectively. With hospital volume (Q4) as a reference, the likelihood of procedural success was lower for Q1 (OR 0.44, 95%CI 0.29-0.68), Q2 (OR 0.50, 95%CI 0.33-0.75) and Q3 (OR 0.60, 95%CI 0.40-0.89); the results were similarly signifant for physician volume. With MAE for hospitals, there was an inverse procedural volume relationship for Q1 (OR 1.78, 95%CI 1.26-2.51) but not for Q2 (OR 1.06, 95%CI 0.77-1.46) or Q3 (OR 1.19, 95%CI 0.89-1.58) and similarly for physicians in Q1 and Q2, not in Q3. An adjusted MAE ≤ 1% was predicted by an annual volume of approximately 190 for hospitals and 60 for physicians. CONCLUSION: In this national cohort, hospital and physician AF ablation procedural volumes were directly related to acute procedural success and inversely related to rates of MAE.

Dual role of proliferating cell nuclear antigen monoubiquitination in facilitating Fanconi anemia-mediated interstrand crosslink repair.

The Fanconi anemia (FA) repair pathway governs repair of highly genotoxic DNA interstrand crosslinks (ICLs) and relies on translesion synthesis (TLS). TLS is facilitated by REV1 or site-specific monoubiquitination of proliferating cell nuclear antigen (PCNA) (PCNA-Ub) at lysine 164 (K164). A PcnaK164R/K164R but not Rev1-/- mutation renders mammals hypersensitive to ICLs. Besides the FA pathway, alternative pathways have been associated with ICL repair (1, 2), though the decision making between those remains elusive. To study the dependence and relevance of PCNA-Ub in FA repair, we intercrossed PcnaK164R/+; Fancg-/+ mice. A combined mutation (PcnaK164R/K164R; Fancg-/- ) was found embryonically lethal. RNA-seq of primary double-mutant (DM) mouse embryonic fibroblasts (MEFs) revealed elevated levels of replication stress-induced checkpoints. To exclude stress-induced confounders, we utilized a Trp53 knock-down to obtain a model to study ICL repair in depth. Regarding ICL-induced cell toxicity, cell cycle arrest, and replication fork progression, single-mutant and DM MEFs were found equally sensitive, establishing PCNA-Ub to be critical for FA-ICL repair. Immunoprecipitation and spectrometry-based analysis revealed an unknown role of PCNA-Ub in excluding mismatch recognition complex MSH2/MSH6 from being recruited to ICLs. In conclusion, our results uncovered a dual function of PCNA-Ub in ICL repair, i.e. exclude MSH2/MSH6 recruitment to channel the ICL toward canonical FA repair, in addition to its established role in coordinating TLS opposite the unhooked ICL.

Characterization of chronic pain, pain interference, and daily pain experiences in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

ABSTRACT: Although survivors of childhood cancer are at an increased risk, little is known about the prevalence of chronic pain, associated interference, and daily pain experiences. Survivors (N = 233; mean age = 40.8 years, range 22-64 years; mean time since diagnosis = 32.7 years) from the Childhood Cancer Survivor Study completed pain and psychosocial measures. Survivors with chronic pain completed 2-week, daily measures assessing pain and psychological symptoms using mHealth-based ecological momentary assessment. Multivariable-modified Poisson and linear regression models estimated prevalence ratio estimates (PR) and mean effects with 95% confidence intervals (CI) for associations of key risk factors with chronic pain and pain interference, respectively. Multilevel mixed models examined outcomes of daily pain and pain interference with prior day symptoms. Ninety-six survivors (41%) reported chronic pain, of whom 23 (24%) had severe interference. Chronic pain was associated with previous intravenous methotrexate treatment (PR = 1.6, 95% CI 1.1-2.3), respiratory (PR = 1.8, 95% CI 1.2-2.5), gastrointestinal (PR = 1.6, 95% CI 11.0-2.3), and neurological (PR = 1.5, 95% CI 1.0-2.1) chronic health conditions, unemployment (PR = 1.4, 95% CI 1.0-1.9) and clinically significant depression and anxiety (PR = 2.9, 95% CI 2.0-4.2), as well as a diagnosis of childhood Ewing sarcoma or osteosarcoma (PR = 1.9, 95% CI 1.0-3.5). Higher pain interference was associated with cardiovascular and neurological conditions, unemployment and clinical levels of depression and/or anxiety, and fear of cancer recurrence. For male, but not female survivors, low sleep quality, elevated anxiety, and elevated depression predicted high pain intensity and interference the next day. A substantial proportion of childhood cancer survivors experience chronic pain and significant associated interference. Chronic pain should be routinely evaluated, and interventions are needed.

A Qualitative Study of National Perspectives on Advancing Social Prescribing Using Co-Design in Canada.

INTRODUCTION: Social prescribing offers a formal pathway of connecting patients in the health system with sources of support within the community to help improve their health and well-being. Since its launch in March 2022, the Canadian Institute for Social Prescribing has acted as a collective impact network to identify, connect and build upon established social prescribing initiatives using a co-design methodology. The institute received input from a participant advisory council, co-design partners and several communities of interest groups. This study aimed to describe the perceptions of the Canadian Institute for Social Prescribing's role in advancing social prescribing using a co-design approach and the barriers and facilitators to implementing social prescribing in Canada. METHODS: We used a qualitative descriptive study design, document analysis, participant observation and semi-structured individual interviews (n = 7) with members of the Canadian Institute for Social Prescribing co-design group and the institute's leadership. We also analysed documents, field notes and transcripts using codebook thematic analysis. RESULTS: Four themes were developed representing the facilitators of implementing the Canadian Institute for Social Prescribing to support social prescribing: Creating relational mechanisms (i.e., partnerships and connections), Bringing awareness to social prescribing and contributing to the evidence (i.e., values and beliefs), Addressing systemic conditions (i.e., having a common language for social prescribing and organizing the community health sector) and Enabling funding and policy to drive social prescribing initiatives (i.e., shifting evidence into policy and securing sustainable funding). CONCLUSION: Participants' reflections on the co-design process demonstrated that the Canadian Institute for Social Prescribing development provided networking opportunities and shared resources relevant to social prescribing. Co-design efforts also fostered relational and informational support, which laid the necessary groundwork in Canada to overcome the complex interplay between the macro- and micro-level settings in which social prescribing is practiced. PATIENT OR PUBLIC CONTRIBUTION: The interviews and observations involved participants with lived experience of delivering, receiving or advocating for social prescribing.

The contribution of E3D imaging integrated with robotic navigation: analysis of the first 80 consecutive posterior spinal fusion cases.

Eighty consecutive complex spinal robotic cases utilizing intraoperative 3D CT imaging (E3D, Group 2) were compared to 80 age-matched controls using the Excelsius robot alone with C-arm Fluoroscopic registration (Robot Only, Group 1). The demographics between the two groups were similar-severity of deformity, ASA Score for general anesthesia, patient age, gender, number of spinal levels instrumented, number of patients with prior spinal surgery, and amount of neurologic compression. The intraoperative CT scanning added several objective factors improving patient safety. There were significantly fewer complications in the E3D group with only 3 of 80 (4%) patients requiring a return to the operating room compared to 11 of 80 (14%) patients in the Robot Only Group requiring repeat surgery for implant related problems (Chi squared analysis = 5.00, p = 0.025). There was a significant reduction the amount of fluoroscopy time in the E3D Group (36 s, range 4-102 s) compared to Robot only group (51 s, range 15-160 s) (p = 0.0001). There was also shorter mean operative time in the E3D group (257 ± 59.5 min) compared to the robot only group (306 ± 73.8 min) due to much faster registration time (45 s). A longer registration time was required in the Robot only group to register each vertebral level with AP and Lateral fluoroscopy shots. The estimated blood loss was also significantly lower in Group 2 (mean 345 ± 225 ml) vs Group 1 (474 ± 397 ml) (p = 0.012). The mean hospital length of stay was also significantly shorter for Group 2 (3.77 ± 1.86 days) compared to Group 1 (5.16 ± 3.40) (p = 0.022). There was no significant difference in the number of interbody implants nor corrective osteotomies in both groups-Robot only 52 cases vs. 42 cases in E3D group.Level of evidence: IV, Retrospective review.

Operationalizing and digitizing person-centered daily functioning: a case for functionomics.

An ever-increasing amount of data on a person's daily functioning is being collected, which holds information to revolutionize person-centered healthcare. However, the full potential of data on daily functioning cannot yet be exploited as it is mostly stored in an unstructured and inaccessible manner. The integration of these data, and thereby expedited knowledge discovery, is possible by the introduction of functionomics as a complementary 'omics' initiative, embracing the advances in data science. Functionomics is the study of high-throughput data on a person's daily functioning, that can be operationalized with the International Classification of Functioning, Disability and Health (ICF).A prerequisite for making functionomics operational are the FAIR (Findable, Accessible, Interoperable, and Reusable) principles. This paper illustrates a step by step application of the FAIR principles for making functionomics data machine readable and accessible, under strictly certified conditions, in a practical example. Establishing more FAIR functionomics data repositories, analyzed using a federated data infrastructure, enables new knowledge generation to improve health and person-centered healthcare. Together, as one allied health and healthcare research community, we need to consider to take up the here proposed methods.

Patient Satisfaction with Nonopioid Postoperative Analgesia in Head and Neck Surgery: A Prospective Randomized Trial.

OBJECTIVE: To evaluate patients' satisfaction with opioid versus opioid-sparing postoperative analgesia in patients undergoing outpatient head and neck surgery. STUDY DESIGN: Prospective randomized trial. SETTING: Tertiary care academic hospital. METHODS: Adult patients undergoing outpatient head and neck surgery were randomly assigned to 1 of 3 analgesic regimens. First- and second-line medications were the following by group (1) Hydrocodone-acetaminophen with ibuprofen, (2) ibuprofen with hydrocodone-acetaminophen, and (3) ibuprofen with acetaminophen. Preoperative counseling was provided to patients regarding expected pain and proper medication use. Postoperative questionnaires were administered to assess satisfaction. RESULTS: One hundred three patients were enrolled in the study (mean age, 56.5 years; women, 75 [73%]). The mean satisfaction score with the pain regimen assigned was similar between the 3 groups (scale 0-10, [7.7, 8.3, 8.5, P = .46]). A similar percentage of patients in each group reported that surgery was more painful than anticipated (25%, 32%, 26%, P = .978), and a similar percentage of patients reported willingness to utilize the same analgesic regimen following future surgeries (75%, 83%, 76%, P = .682). Additional questions evaluating the side effect profile, maximum and minimum pain scores, and difficulty of recovery were not statistically different between the 3 groups. CONCLUSION: In the postoperative population for outpatient head and neck surgeries, there was no significant difference in patient satisfaction and pain control between the opioid and nonopioid arms. Providers should discuss opioid-sparing regimens preoperatively with patients and describe them as effective in providing adequate pain control without a significant impact on patient's perception of care.

For the Love of the Game: Calculating the Premium Associated with Academic Surgical Practice.

OBJECTIVE: We sought to determine the premium associated with a career in academic surgery, as measured by compensation normalized to the work relative value unit (wRVU). BACKGROUND: An academic surgical career, embodying innovation and mentorship, offers intrinsic rewards, but is not well monetized. We know compensation for academic surgeons is less than their non-academic counterparts, but the value of clinical effort, as normalized to the wRVU, between academic and non-academic surgeons has not been well characterized. Thus, we analyzed the variations in the valuation of academic and non-academic surgical work from 2010 to 2022. METHODS: We utilized Medical Group Management Association Provider Compensation data from 2010, 2014, 2018, and 2022 to compare academic and non-academic surgeons. We analyzed raw total cash compensation (TCC), wRVU, TCC per wRVU (TCC/wRVU), and TCC to collections (TCCtColl). We calculated collections per wRVU (Coll/wRVU). We adjusted TCC and TCCtColl for inflation using the Consumer Price Index. Linear modeling for trend analysis was performed. RESULTS: Compared to non-academic, academic surgeons had lower TCC (2010: $500,415.0±23,666 vs. $631,515.5±23,948.2, -21%; 2022: $564,789.8±23,993.9 vs. $628,247.4±15,753.2, -10%), despite higher wRVUs (2022: 9,109.4±474.9 vs. 8,062.7±252.7) and higher Coll/wRVU (2022: 76.68±8.15 vs. 71.80±6.10). Trend analysis indicated TCC will converge in 2038 at an estimated $660,931. CONCLUSIONS: In 2022, academic surgeons had more clinical activity and superior organizational revenue capture, despite less total and normalized clinical compensation. Based on TCC/wRVUs, academia charges a premium of 16% over non-academic surgery. However, trend analysis suggests that TCC will converge within the next twenty years.

Clinical Applications of Machine Learning.

Objective: This review introduces interpretable predictive machine learning approaches, natural language processing, image recognition, and reinforcement learning methodologies to familiarize end users. Background: As machine learning, artificial intelligence, and generative artificial intelligence become increasingly utilized in clinical medicine, it is imperative that end users understand the underlying methodologies. Methods: This review describes publicly available datasets that can be used with interpretable predictive approaches, natural language processing, image recognition, and reinforcement learning models, outlines result interpretation, and provides references for in-depth information about each analytical framework. Results: This review introduces interpretable predictive machine learning models, natural language processing, image recognition, and reinforcement learning methodologies. Conclusions: Interpretable predictive machine learning models, natural language processing, image recognition, and reinforcement learning are core machine learning methodologies that underlie many of the artificial intelligence methodologies that will drive the future of clinical medicine and surgery. End users must be well versed in the strengths and weaknesses of these tools as they are applied to patient care now and in the future.

The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma.

Comprehensive m6A epitranscriptome profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 non-neoplastic lung (NL) tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating the corresponding transcriptome, proteome and extensive clinical annotations. We identified distinct clusters and genes that were exclusively linked to disease progression through m6A modifications. In comparison with NL tissues, we identified 430 transcripts to be hypo-methylated and 222 to be hyper-methylated in tumors. Among these genes, EML4 emerged as a novel metastatic driver, displaying significant hyper-methylation in tumors. m6A modification promoted the translation of EML4, leading to its widespread overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics through interacting with ARPC1A, enhancing lamellipodia formation, cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. METTL3 small molecule inhibitor markedly diminished both EML4 m6A and protein abundance, and efficiently suppressed lung metastases in vivo.

Structural basis for inhibition of coagulation factor VIII reveals a shared antigenic hotspot on the C1 domain.

BACKGROUND: Hemophilia A arises from dysfunctional or deficient coagulation factor (F)VIII and leads to inefficient fibrin clot formation and uncontrolled bleeding events. The development of antibody inhibitors is a clinical complication in hemophilia A patients receiving FVIII replacement therapy. LE2E9 is an anti-C1 domain inhibitor previously isolated from a mild/moderate hemophilia A patient and disrupts FVIII interactions with von Willebrand factor and FIXa, though the intermolecular contacts that underpin LE2E9-mediated FVIII neutralization are undefined. OBJECTIVES: To determine the structure of the complex between FVIII and LE2E9 and characterize its mechanism of inhibition. METHODS: FVIII was bound to the antigen binding fragment (Fab) of NB2E9, a recombinant construct of LE2E9, and its structure was determined by cryogenic electron microscopy. RESULTS: This report communicates the 3.46 Å structure of FVIII bound to NB2E9, with its epitope comprising FVIII residues S2040 to Y2043, K2065 to W2070, and R2150 to H2155. Structural analysis reveals that the LE2E9 epitope overlaps with portions of the epitope for 2A9, a murine-derived inhibitor, suggesting that these residues represent a shared antigenic region on the C1 domain between FVIII-/- mice and hemophilia A patients. Furthermore, the FVIII:NB2E9 structure elucidates the orientation of the LE2E9 glycan, illustrating how the glycan sterically blocks interactions between the FVIII C1 domain and the von Willebrand factor D' domain. A putative model of the FVIIIa:FIXa complex suggests potential clashing between the NB2E9 glycan and FIXa light chain. CONCLUSION: These results describe an antigenic "hotspot" on the FVIII C1 domain and provide a structural basis for engineering FVIII replacement therapeutics with reduced antigenicity.

Artificial intelligence-based epigenomic, transcriptomic and histologic signatures of tobacco use in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) biomarker studies rarely employ multi-omic biomarker strategies and pertinent clinicopathologic characteristics to predict mortality. In this study we determine for the first time a combined epigenetic, gene expression, and histology signature that differentiates between patients with different tobacco use history (heavy tobacco use with ≥10 pack years vs. no tobacco use). Using The Cancer Genome Atlas (TCGA) cohort (n = 257) and an internal cohort (n = 40), we identify 3 epigenetic markers (GPR15, GNG12, GDNF) and 13 expression markers (IGHA2, SCG5, RPL3L, NTRK1, CD96, BMP6, TFPI2, EFEMP2, RYR3, DMTN, GPD2, BAALC, and FMO3), which are dysregulated in OSCC patients who were never smokers vs. those who have a ≥ 10 pack year history. While mortality risk prediction based on smoking status and clinicopathologic covariates alone is inaccurate (c-statistic = 0.57), the combined epigenetic/expression and histologic signature has a c-statistic = 0.9409 in predicting 5-year mortality in OSCC patients.

Dimensional Scaling of Ferroelectric Properties of Hafnia-Zirconia Thin Films: Electrode Interface Effects.

Hafnia-based ferroelectric (FE) thin films are promising candidates for semiconductor memories. However, a fundamental challenge that persists is the lack of understanding regarding dimensional scaling, including thickness scaling and area scaling, of the functional properties and their heterogeneity in these films. In this work, excellent ferroelectricity and switching endurance are demonstrated in 4 nm-thick Hf0.5Zr0.5O2 (HZO) capacitors with molybdenum electrodes in capacitors as small as 65 nm × 45 nm in size. The HZO layer in these capacitors can be crystallized into the ferroelectric orthorhombic phase at the low temperature of 400 °C, making them compatible for back-end-of-line (BEOL) FE memories. With the benefits of thickness scaling, low operation voltage (1.2 V) is achieved with high endurance (>1010 cycles); however, a significant fatigue regime is noted. We observed that the bottom electrode, rather than the top electrode, plays a dominant role in the thickness scaling of HZO ferroelectric behavior. Furthermore, ultrahigh switched polarization (remanent polarization 2Pr ∼ 108 µC cm-2) is observed in some nanoscale devices. This study advances the understanding of dimensional scaling effects in HZO capacitors for high-performance FE memories.

Developments in anticorrosive organic coatings modulated by nano/microcontainers with porous matrices.

The durability and functionality of many metallic structures are seriously threatened by corrosion, which makes the development of anticorrosive coatings imperative. This state-of-the-art survey explores the recent developments in the field of anticorrosive organic coatings modulated by innovations involving nano/microcontainers with porous matrices. The integration of these cutting-edge delivery systems seeks to improve the protective properties of coatings by enabling controlled release, extended durability, targeted application of corrosion inhibitors, and can be co-constructed to achieve defect filling by polymeric materials. The major highlight of this review is an in-depth analysis of the functionalities provided by porous nano/microcontainers in the active protection and self-healing of anticorrosive coatings, including their performance evaluation. In one case, after 20 days of immersion in 0.1 M NaCl, a scratched coating containing mesoporous silica nanoparticles loaded with an inhibitor benzotriazole and shelled with polydopamine (MSNs-BTA@PDA) exhibited coating restoration indicated by a sustained corrosion resistance rise over an extended period monitored by impedance values at 0.01 Hz frequency, rising from 8.3 × 104 to 7.0 × 105 Ω cm2, a trend assigned to active protection by the release of inhibitors and self-healing capabilities. Additionally, some functions related to anti-fouling and heat preservation by nano/microcontainers are highlighted. Based on the literature survey, some desirable properties, current challenges, and prospects of anticorrosive coatings doped with nano/microcontainers have been summarized. The knowledge gained from this survey will shape future research directions and applications in a variety of industrial areas, in addition to advancing smart corrosion prevention technology.

Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E-deficient mice.

Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg-1·d-1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50 µM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE-/- mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis.

Incorporating Molecular Data Into Treatment Decision Making in Gastroesophageal and Pancreaticobiliary Cancers: Timing and Strategies.

Gastroesophageal (GE) and pancreatobiliary (PB) cancers represent a significant clinical challenge. In this context, it is critical to understand the key molecular targets within these malignancies including how they are assayed for as well as the clinical actionability of these targets. Integrating biomarkers into the standard of care presents a critical avenue for refining treatment paradigms. This review aims to explore these complexities, offering insights into the optimal sequencing of chemotherapy and targeted therapies and their utility in the management of GE and PB cancers. The timely integration of promising investigational therapies into clinical practice has broader implications around strategies for future clinical trial designs, which would pave the way for advancements in the management of GE and PB cancers. This review provides guidance in navigating the evolving landscape of GE and PB cancer care, which ultimately will drive forward progress in the field and lead to improved patient outcomes.

Impact of Obesity on Timing of Tracheotomy: A Multi-institutional Retrospective Study.

OBJECTIVE: To examine the impact of increased body mass index (BMI) on (1) tracheotomy timing and (2) short-term surgical complications requiring a return to the operating room and 30-day mortality utilizing data from the Multi-Institutional Study on Tracheotomy (MIST). METHODS: A retrospective analysis of patients from the MIST database who underwent surgical or percutaneous tracheotomy between 2013 and 2016 at eight institutions was completed. Unadjusted and adjusted logistic regression analyses were used to assess the impact of obesity on tracheotomy timing and complications. RESULTS: Among the 3369 patients who underwent tracheotomy, 41.0% were obese and 21.6% were morbidly obese. BMI was associated with higher rates of prolonged intubation prior to tracheotomy accounting for comorbidities, indication for tracheotomy, institution, and type of tracheostomy (p = 0.001). Morbidly obese patients (BMI ≥35 kg/m2) experienced a longer duration of intubation compared with patients with a normal BMI (median days intubated [IQR 25%-75%]: 11.0 days [7-17 days] versus 9.0 days [5-14 days]; p < 0.001) but did not have statistically higher rates of return to the operating room within 30 days (p = 0.12) or mortality (p = 0.90) on multivariable analysis. This same finding of prolonged intubation was not seen in overweight, nonobese patients when compared with normal BMI patients (median days intubated [IQR 25%-75%]: 10.0 days [6-15 days] versus 10.0 days [6-15 days]; p = 0.36). CONCLUSION: BMI was associated with increased duration of intubation prior to tracheotomy. Although morbidly obese patients had a longer duration of intubation, there were no differences in return to the operating room or mortality within 30 days. LEVEL OF EVIDENCE: III Laryngoscope, 2024.

The effectiveness of a protocol without routine radiographs for follow-up of adolescent idiopathic scoliosis patients (CURVE): a study protocol.

BACKGROUND AND PURPOSE: Current follow-up protocols for adolescent idiopathic scoliosis (AIS) are based on consensus and consist of regular full-spine radiographs to monitor curve progression and surgical complications. Consensus exists to avoid inappropriate use of radiographs in children. It is unknown whether a standard radiologic follow-up (S-FU) approach is necessary or if a patient-empowered follow-up (PE-FU) approach can reduce the number of radiographs without treatment consequences. METHODS AND ANALYSES: A nationwide multicenter pragmatic randomized preference trial was designed for 3 follow-up subgroups (pre-treatment, post-brace, post-surgery) to compare PE-FU and S-FU. 812 patients with AIS (age 10-18 years) will be included in the randomized trial or preference cohorts. Primary outcome is the proportion of radiographs with a treatment consequence for each subgroup. Secondary outcomes consist of the proportion of patients with delayed initiation of treatment due to non-routine radiographic follow-up, radiation exposure, societal costs, positive predictive value, and interrelation of clinical assessment, quality of life, and parameters for initiation of treatment during follow-up. Outcomes will be analyzed using linear mixed-effects models, adjusted for relevant baseline covariates, and are based on intention-to-treat principle. Study summary: (i) a national, multicenter pragmatic randomized trial addressing the optimal frequency of radiographic follow-up in patients with AIS; (ii) first study that includes patient-empowered follow-up; (iii) an inclusive study with 3 follow-up subgroups and few exclusion criteria representative for clinical reality; (iv) preference cohorts alongside to amplify generalizability; (v) first study conducting an economic evaluation comparing both follow-up approaches.