Long-term impact of artificial intelligence on colorectal adenoma detection in high-risk colonoscopy.

BACKGROUND: Improved adenoma detection rate (ADR) has been demonstrated with artificial intelligence (AI)-assisted colonoscopy. However, data on the real-world application of AI and its effect on colorectal cancer (CRC) screening outcomes is limited. AIM: To analyze the long-term impact of AI on a diverse at-risk patient population undergoing diagnostic colonoscopy for positive CRC screening tests or symptoms. METHODS: AI software (GI Genius, Medtronic) was implemented into the standard procedure protocol in November 2022. Data was collected on patient demographics, procedure indication, polyp size, location, and pathology. CRC screening outcomes were evaluated before and at different intervals after AI introduction with one year of follow-up. RESULTS: We evaluated 1008 colonoscopies (278 pre-AI, 255 early post-AI, 285 established post-AI, and 190 late post-AI). The ADR was 38.1% pre-AI, 42.0% early post-AI (P = 0.77), 40.0% established post-AI (P = 0.44), and 39.5% late post-AI (P = 0.77). There were no significant differences in polyp detection rate (PDR, baseline 59.7%), advanced ADR (baseline 16.2%), and non-neoplastic PDR (baseline 30.0%) before and after AI introduction. CONCLUSION: In patients with an increased pre-test probability of having an abnormal colonoscopy, the current generation of AI did not yield enhanced CRC screening metrics over high-quality colonoscopy. Although the potential of AI in colonoscopy is undisputed, current AI technology may not universally elevate screening metrics across all situations and patient populations. Future studies that analyze different AI systems across various patient populations are needed to determine the most effective role of AI in optimizing CRC screening in clinical practice.

Evaluation and application of American College of Radiology Thyroid Imaging Reporting and Data System for improved malignancy detection in paediatric thyroid nodules.

OBJECTIVE: The American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) is a widely used method for the management of adult thyroid nodules. However, its use in paediatric patients is controversial because adult fine needle aspiration biopsy (FNAB) recommendations may lead to delayed diagnoses of cancer in children. The objectives of this study were to evaluate the performance of TI-RADS in paediatric thyroid nodules and to tailor FNAB recommendations for children. METHODS: Consecutive surgically resected paediatric thyroid nodules from two tertiary care centres between 2003 and 2021 were reviewed. Ultrasounds were blindly scored by radiologists according to TI-RADS. Management recommendations based on TI-RADS were evaluated. Various modelling methodologies were used to determine the optimal cutoff for FNAB in children. RESULTS: Of the 96 patients, 79 (82%) were female and the median age at surgery was 16.1 years. Fifty (52%) nodules were malignant on surgical pathology. The area under the receiver operating characteristic curve of TI-RADS for predicting malignancy was 0.78. Adult TI-RADS recommendations would have resulted in 4% of cancerous nodules being lost to follow-up. Modifications to TI-RADS (FNAB of all TR3 nodules ≥1.5 cm, FNAB of TR4 and TR5 nodules ≥0.5 cm, surveillance of nodules ≥1 cm, consider surgery for nodules >4 cm) reduced this missed malignancy rate to 0%. CONCLUSIONS: TI-RADS can risk-stratify paediatric thyroid nodules. However, the system requires modifications to reduce the missed malignancy rate in paediatric thyroid nodules. Our data suggest that lower size thresholds for FNAB are warranted in children.

Revealing Structural Evolution of Nickel Phosphide-Iron Oxide Core-Shell Nanocatalysts in Alkaline Medium for the Oxygen Evolution Reaction.

Metal phosphide-containing materials have emerged as a potential candidate of nonprecious metal-based catalysts for alkaline oxygen evolution reaction (OER). While it is known that metal phosphide undergoes structural evolution, considerable debate persists regarding the effects of dynamics on the surface activation and morphological stability of the catalysts. In this study, we synthesize NiP x -FeO x core-shell nanocatalysts with an amorphous NiP x core designed for enhanced OER activity. Using ex situ X-ray absorption spectroscopy, we elucidate the local structural changes as a function of the cyclic voltammetry cycles. Our studies suggest that the presence of corner-sharing octahedra in the FeO x shell improves structural rigidity through interlayer cross-linking, thereby inhibiting the diffusion of OH-/H2O. Thus, the FeO x shell preserves the amorphous NiP x core from rapid oxidation to Ni3(PO4)2 and Ni(OH)2. On the other hand, the incorporation of Ni from the core into the FeO x shell facilitates absorption of hydroxide ions for OER. As a result, Ni/Fe(OH) x at the surface oxidizes to the active γ-(oxy)hydroxide phase under the applied potentials, promoting OER. This intriguing synergistic behavior holds significance as such a synthetic route involving the FeO x shell can be extended to other systems, enabling manipulation of surface adsorption and diffusion of hydroxide ions. These findings also demonstrate that nanomaterials with core-shell morphologies can be tuned to leverage the strength of each metallic component for improved electrochemical activities.

Innovative Strategies for Addressing Adolescent Health in Primary Care Through Telehealth.

With recent gains in telehealth access across health sectors, this editorial explores adolescent-specific health issues where innovative use of virtual care is improving outcomes and access for adolescents. These include contraception, obesity, gender-affirming care, mental health, and eating disorder care. Clinicians caring for adolescents should be aware of advances in this field to maximize opportunities for their patients to receive evidence-based care in a manner that supports health equity and confidentiality concerns while understanding the evolving regulatory landscape of telehealth.

Self-deployable contracting-cord metamaterials with tunable mechanical properties.

Recent advances in active materials and fabrication techniques have enabled the production of cyclically self-deployable metamaterials with an expanded functionality space. However, designing metamaterials that possess continuously tunable mechanical properties after self-deployment remains a challenge, notwithstanding its importance. Inspired by push puppets, we introduce an efficient design strategy to create reversibly self-deployable metamaterials with continuously tunable post-deployment stiffness and damping. Our metamaterial comprises contracting actuators threaded through beads with matching conical concavo-convex interfaces in networked chains. The slack network conforms to arbitrary shapes, but when actuated, it self-assembles into a preprogrammed configuration with beads gathered together. Further contraction of the actuators can dynamically tune the assembly's mechanical properties through the beads' particle jamming, while maintaining the overall structure with minimal change. We show that, after deployment, such metamaterials exhibit pronounced tunability in bending-dominated configurations: they can become more than 35 times stiffer and change their damping capability by over 50%. Through systematic analysis, we find that the beads' conical angle can introduce geometric nonlinearity, which has a major effect on the self-deployability and tunability of the metamaterial. Our work provides routes towards reversibly self-deployable, lightweight, and tunable metamaterials, with potential applications in soft robotics, reconfigurable architectures, and space engineering.

Spatial transcriptomics reveals influence of microenvironment on intrinsic fates in melanoma therapy resistance.

Resistance to cancer therapy is driven by both cell-intrinsic and microenvironmental factors. Previous work has revealed that multiple resistant cell fates emerge in melanoma following treatment with targeted therapy and that, in vitro, these resistant fates are determined by the transcriptional state of individual cells prior to exposure to treatment. What remains unclear is whether these resistant fates are shared across different genetic backgrounds and how, if at all, these resistant fates interact with the tumor microenvironment. Through spatial transcriptomics and single-cell RNA sequencing, we uncovered distinct resistance programs in melanoma cells shaped by both intrinsic cellular states and the tumor microenvironment. Consensus non-negative matrix factorization revealed shared intrinsic resistance programs across different cell lines, highlighting the presence of universal and unique resistance pathways. In patient samples, we demonstrated that these resistance programs coexist within individual tumors and associate with diverse immune signatures, suggesting that the tumor microenvironment and distribution of resistant fates are closely connected. Single-cell resolution spatial transcriptomics in xenograft models revealed both intrinsically determined and extrinsically influenced resistant fates. Overall, this work demonstrates that each therapy resistant fate coexists with a distinct immune microenvironment in tumors and that, in vivo, tissue features, such as regions of necrosis, can influence which resistant fate is adopted.

Is Suffering a Useless Concept?

"Suffering" is a central concept within bioethics and often a crucial consideration in medical decision making. As used in practice, however, the concept risks being uninformative, ambiguous, or even misleading. In this paper, we consider a series of cases in which "suffering" is invoked and analyze them in light of prominent theories of suffering. We then outline ethical hazards that arise as a result of imprecise usage of the concept and offer practical recommendations for avoiding them. Appeals to suffering are often getting at something ethically important. But this is where the work of ethics begins, not where it ends.

Epithelial IL-2 is critical for NK cell-mediated cancer immunosurveillance in mammary glands.

Interleukin 2 (IL-2) is the first identified cytokine and its interaction with receptors has been known to shape the immune responses in many lymphoid or non-lymphoid tissues for more than four decades. Active T cells are the primary cellular source for IL-2 production and epithelial cells have never been considered the major cellular source of IL-2 under physiological conditions. It is, however, tempting to speculate that epithelial cells could potentially express IL-2 that regulates the intricate interactions between epithelial cells and lymphocytes. Datamining our recently published single-cell RNAseq in the mouse mammary gland identified IL-2 expression in mammary epithelial cells, which is induced by prolactin via the STAT5 signaling pathway. Furthermore, epithelial IL-2 plays a crucial role in maintaining the physiological functions of natural killer (NK) cells within the mammary glands. IL-2 deletion in the mammary epithelial cells leads to a significant reduction in the number and function of NK cells, which in turn results in defective immunosurveillance, expansion of luminal epithelial cells, and tumor development. Interestingly, T cells in the mammary glands are not changed, indicating the specific regulation of NK cells by epithelial IL-2 production. In agreement, we also found that human epithelial cells express IL-2 and NK cells express the highest level of IL2RB among all the immune cells. Here, we provide the first evidence that epithelial cells produce IL-2, which is critical for maintaining the physiological functions of NK cells in immunosurveillance.

Pre-Operative Characteristics Helping to Avoid Gastrostomy Tube After Mandibular Distraction in Neonates With Pierre-Robin Sequence: A Institutional Case-Series and Review of the Literature.

OBJECTIVE: to investigate the ability of mandibular distraction osteogenesis (MDO) to avoid gastrostomy tube (G-tube). DATA SOURCES: PubMed, EBSCOhost, Cochrane, and Embase. REVIEW METHODS: We retrospectively reviewed the number of MDO cases performed at our institution for patients with Robin Sequence (RS) over the past 10 years. In our institutional review, patients were excluded if they had a G-tube already placed at the time of surgery. We also performed a systematic review of the literature. Articles were excluded if they did not detail feeding outcomes after MDO, or if MDO was performed on patients that did not have RS. RESULTS: In our systematic review, 12 articles were included that comprised a total of 209 neonates with RS that underwent MDO. A total of 174 (83.3%) patients avoided a G-tube once MDO was performed. A total of 14 patients met the inclusion criteria at our institution. Of the 14 RS patients, 9 (64%) avoided having a G-tube placed and all (14/14) avoided tracheostomy. The average birth weight of patients avoiding a G-tube was 3.11 kg compared to 2.25 kg (P = .045) in the group requiring a G-tube. In the group avoiding a G-tube, the average weight at time of operation was 3.46 kg compared to 2.83 kg (P = .037) in the group requiring a G-tube. CONCLUSION: MDO may be considered as a surgical option to prevent G-tube placement for neonates with non-syndromic RS who have difficulty with PO feeding but whose airway obstruction is not severe enough to require respiratory support. Based on our institutional experience, a minimum weight of 3.00 kg correlated with higher success rates of PO intake and avoiding a G-tube.

Molecular Landscape and Clinical Implication of CCNE1-amplified Esophagogastric Cancer.

Cyclin E overexpression as a result of CCNE1 amplification is a critical driver of genomic instability in gastric cancer, but its clinical implication is largely unknown. Thus, we integrated genomic, transcriptomic, and immune profiling analysis of 7,083 esophagogastric tumors and investigated the impact of CCNE1 amplification on molecular features and treatment outcomes. We identified CCNE1 amplification in 6.2% of esophageal adenocarcinoma samples, 7.0% of esophagogastric junction carcinoma, 4.2% of gastric adenocarcinoma samples, and 0.8% of esophageal squamous cell carcinoma. Metastatic sites such as lymph node and liver showed an increased frequency of CCNE1 amplification relative to primary tumors. Consistent with a chromosomal instability phenotype, CCNE1 amplification was associated with decreased CDH1 mutation and increased TP53 mutation and ERBB2 amplification. We observed no differences in immune biomarkers such as PD-L1 expression and tumor mutational burden comparing CCNE1-amplified and nonamplified tumors, although CCNE1 amplification was associated with changes in immune populations such as decreased B cells and increased M1 macrophages from transcriptional analysis. Real-world survival analysis demonstrated that patients with CCNE1-amplified gastric cancer had worse survival after trastuzumab for HER2-positive tumors, but better survival after immunotherapy. These data suggest that CCNE1-amplified gastric cancer has a distinct molecular and immune profile with important therapeutic implications, and therefore further investigation of CCNE1 amplification as a predictive biomarker is warranted. SIGNIFICANCE: Advanced gastric cancer has a relatively dismal outcome with a 5-year overall survival of less than 10%. Furthermore, while comprehensive molecular analyses have established molecular subtypes within gastric cancers, biomarkers of clinical relevance in this cancer type are lacking. Overall, this study demonstrates that CCNE1 amplification is associated with a distinct molecular profile in gastric cancer and may impact response to therapy, including targeted therapy and/or immunotherapy.

Bitter taste receptor activation by cholesterol and an intracellular tastant.

Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors1. Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants2-6, although the molecular mechanisms for recognizing diverse chemicals and initiating cellular signalling are still poorly understood. Here we report two cryo-electron microscopy structures for TAS2R14 complexed with Ggust (also known as gustducin) and Gi1. Both structures have an orthosteric binding pocket occupied by endogenous cholesterol as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1, including a direct interaction with the α5 helix of Ggust and Gi1. Computational and biochemical studies validate both ligand interactions. Our functional analysis identified cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator with direct agonist activity at TAS2R14. Moreover, the orthosteric pocket is connected to the allosteric site via an elongated cavity, which has a hydrophobic core rich in aromatic residues. Our findings provide insights into the ligand recognition of bitter taste receptors and suggest activities of TAS2R14 beyond bitter taste perception via intracellular allosteric tastants.

Repair of Full-Thickness Gluteus Maximus Tear With Suture Anchors.

Gluteal tendon tears are a common cause of hip pain. Most commonly, tears occur in the gluteus medius and minimus, and there are well-established nonoperative or operative treatment pathways. In this Technical Note, we describe our technique for repair of a full-thickness gluteus maximus tendon tear using anchor fixation.

Same-Day Discharge for Pediatric Hemithyroidectomy Patients: Evaluating Safety and Barriers to Discharge.

OBJECTIVE: Hemithyroidectomy is often performed in the pediatric population for indeterminate or benign thyroid nodules. Prior studies confirmed the safety of same-day discharge for adults undergoing hemithyroidectomy or total thyroidectomy, but this has not been studied thoroughly in the pediatric population. Our goal was to determine differences in pediatric patients undergoing hemithyroidectomy who were admitted versus discharged for complications or factors to support same-day discharge. STUDY DESIGN: Retrospective cohort. SETTING: Pediatric tertiary care hospital. METHODS: This was a retrospective study of pediatric patients (0-18 years of age) undergoing hemithyroidectomy at a pediatric tertiary care hospital from 2003 to 2022. Perioperative variables and outcomes were gathered via manual chart review. RESULTS: One hundred five pediatric patients who underwent hemithyroidectomy were identified. Ninety (86%) patients were admitted postoperatively, and 15 (14%) were discharged the same day. There were no differences in patient demographics, including age (P = 0.29) distance from the hospital (P = 0.08) or benign versus malignant pathology (P = 0.93). Surgical time in same-day discharges was significantly shorter (P = 0.0001; 138.6 minutes, SD = 66.0) versus admitted patients (204.2 minutes, SD = 48.6) Hemostatic agents were used more in same-day discharges at 53.3% versus 4.5% (P = 0.0001). Perioperative complications occurred in 2 (2.2%) admitted patients compared to none in the same-day discharge (P = 1.0). There were no readmissions within 30 days for same-day discharges. CONCLUSION: In pediatric patients undergoing uncomplicated hemithyroidectomy, same-day discharge appears appropriate for those with shorter surgical times and intraoperative use of hemostatic agents with no readmissions or complications in those discharged the same day.

Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases.

Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a therapeutic strategy for treatment of neurodegenerative diseases such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS) based on its ability to improve cellular homeostasis and prevent neuronal degeneration. Herein, we report the small-molecule discovery campaign that identified potent, selective, and CNS-penetrant eIF2B activators using both structure- and ligand-based drug design. These discovery efforts culminated in the identification of DNL343, which demonstrated a desirable preclinical drug profile, including a long half-life and high oral bioavailability across preclinical species. DNL343 was progressed into clinical studies and is currently undergoing evaluation in late-stage clinical trials for ALS.

ctDNA transiting into urine is ultrashort and facilitates noninvasive liquid biopsy of HPV+ oropharyngeal cancer.

BACKGROUNDTransrenal cell-free tumor DNA (TR-ctDNA), which transits from the bloodstream into urine, has the potential to enable noninvasive cancer detection for a wide variety of nonurologic cancer types.MethodsUsing whole-genome sequencing, we discovered that urine TR-ctDNA fragments across multiple cancer types are predominantly ultrashort (<50 bp) and, therefore, likely to be missed by conventional ctDNA assays. We developed an ultrashort droplet digital PCR assay to detect TR-ctDNA originating from HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC) and confirmed that assaying ultrashort DNA is critical for sensitive cancer detection from urine samples.ResultsTR-ctDNA was concordant with plasma ctDNA for cancer detection in patients with HPV+ OPSCC. As proof of concept for using urine TR-ctDNA for posttreatment surveillance, in a small longitudinal case series, TR-ctDNA showed promise for noninvasive detection of recurrence of HPV+ OPSCC.ConclusionOur data indicate that focusing on ultrashort fragments of TR-ctDNA will be important for realizing the full potential of urine-based cancer diagnostics. This has implications for urine-based detection of a wide variety of cancer types and for facilitating access to care through at-home specimen collections.FundingNIH grants R33 CA229023, R21 CA225493; NIH/National Cancer Institute grants U01 CA183848, R01 CA184153, and P30CA046592; American Cancer Society RSG-18-062-01-TBG; American Cancer Society Mission Boost grant MBGI-22-056-01-MBG; and the A. Alfred Taubman Medical Research Institute.