A Case of Osseous Metaplasia in a Juvenile Rectal Polyp.

Rectal mucosal prolapse is uncommon in children. While most patients present with rectal bleeding and constipation, the occurrence of osseous metaplasia within the prolapsed mucosa is extremely rare. Overlapping clinical, gross, and histological features between rectal mucosal prolapse polyps and malignancy pose a challenge for diagnoses. We describe a case of a 16-year-old male who had a rectal mucosal prolapsed polyp with osseous metaplasia. He initially presented due to periumbilical pain with a sore throat and fever. Incidentally, during the workup of his periumbilical pain, he was found to have a soft tissue mass in his rectum on a CT scan, with a biopsy confirming the diagnosis. The case was complicated by the development of sepsis. The patient was treated with empiric antibiotics and was discharged without further complications.

Assessing the agreement of chronic lung disease of prematurity diagnosis between radiologists and clinical criteria.

BACKGROUND: Chronic lung disease of prematurity (CLD) is the most prevalent complication of preterm birth and indicates an increased likelihood of long-term pulmonary complications. The accurate diagnosis of this condition is critical for long-term health management. Numerous definitions define CLD with different clinical parameters and radiology findings, making diagnosis of the disease ambiguous and potentially inaccurate. METHODS: 95 patients were identified for this study, as determined by the diagnosis or confirmation of CLD in the impression of the radiologist's report on chest x-ray. Pulmonary function and complications were recorded at multiple benchmark timeframes within each patient's first few months of life and used for determining eligibility under each definition. RESULTS: Each clinical definition of CLD had a high sensitivity for patients identified to have CLD by radiologists, correctly fitting over 90% of patients. Most patients included required invasive mechanical ventilation or positive pressure ventilation at 36 weeks postmenstrual age, indicating patients with radiographically confirmed CLD tended to have more severe disease. Radiologists tended to diagnose CLD before 36 weeks postmenstrual age, a timepoint used by multiple standard clinical definitions, with cases called earlier fitting under a larger percentage of definitions than those called later. CONCLUSIONS: Radiologists tend to diagnose CLD in young patients with severe respiratory compromise, and can accurately diagnose the condition before developmental milestones for clinical definitions are met.

trans-Endothelial neutrophil migration activates bactericidal function via Piezo1 mechanosensing.

The regulation of polymorphonuclear leukocyte (PMN) function by mechanical forces encountered during their migration across restrictive endothelial cell junctions is not well understood. Using genetic, imaging, microfluidic, and in vivo approaches, we demonstrated that the mechanosensor Piezo1 in PMN plasmalemma induced spike-like Ca2+ signals during trans-endothelial migration. Mechanosensing increased the bactericidal function of PMN entering tissue. Mice in which Piezo1 in PMNs was genetically deleted were defective in clearing bacteria, and their lungs were predisposed to severe infection. Adoptive transfer of Piezo1-activated PMNs into the lungs of Pseudomonas aeruginosa-infected mice or exposing PMNs to defined mechanical forces in microfluidic systems improved bacterial clearance phenotype of PMNs. Piezo1 transduced the mechanical signals activated during transmigration to upregulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4, crucial for the increased PMN bactericidal activity. Thus, Piezo1 mechanosensing of increased PMN tension, while traversing the narrow endothelial adherens junctions, is a central mechanism activating the host-defense function of transmigrating PMNs.

The Rapid Development of Artificial Intelligence: GPT-4's Performance on Orthopedic Surgery Board Questions.

Advances in artificial intelligence and machine learning models, like Chat Generative Pre-trained Transformer (ChatGPT), have occurred at a remarkably fast rate. OpenAI released its newest model of ChatGPT, GPT-4, in March 2023. It offers a wide range of medical applications. The model has demonstrated notable proficiency on many medical board examinations. This study sought to assess GPT-4's performance on the Orthopaedic In-Training Examination (OITE) used to prepare residents for the American Board of Orthopaedic Surgery (ABOS) Part I Examination. The data gathered from GPT-4's performance were additionally compared with the data of the previous iteration of ChatGPT, GPT-3.5, which was released 4 months before GPT-4. GPT-4 correctly answered 251 of the 396 attempted questions (63.4%), whereas GPT-3.5 correctly answered 46.3% of 410 attempted questions. GPT-4 was significantly more accurate than GPT-3.5 on orthopedic board-style questions (P<.00001). GPT-4's performance is most comparable to that of an average third-year orthopedic surgery resident, while GPT-3.5 performed below an average orthopedic intern. GPT-4's overall accuracy was just below the approximate threshold that indicates a likely pass on the ABOS Part I Examination. Our results demonstrate significant improvements in OpenAI's newest model, GPT-4. Future studies should assess potential clinical applications as AI models continue to be trained on larger data sets and offer more capabilities. [Orthopedics. 2024;47(2):e85-e89.].

Spatially resolved detection of small molecules from press-dried plant tissue using MALDI imaging.

Premise: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) is a chemical imaging method that can visualize spatial distributions of particular molecules. Plant tissue imaging has so far mostly used cryosectioning, which can be impractical for the preparation of large-area imaging samples, such as full flower petals. Imaging unsectioned plant tissue presents its own difficulties in extracting metabolites to the surface due to the waxy cuticle. Methods: We address this by using established delipidation techniques combined with a solvent vapor extraction prior to applying the matrix with many low-concentration sprays. Results: Using this procedure, we imaged tissue from three different plant species (two flowers and one carnivorous plant leaf). Material factorization analysis of the resulting data reveals a wide range of plant-specific small molecules with varying degrees of localization to specific portions of the tissue samples, while facilitating detection and removal of signal from background sources. Conclusions: This work demonstrates applicability of MALDI-MSI to press-dried plant samples without freezing or cryosectioning, setting the stage for spatially resolved molecule identification. Increased mass resolution and inclusion of tandem mass spectrometry are necessary next steps to allow more specific and reliable compound identification.

Premisa: Matrix­assisted laser desorption/ionization mass spectrometry imaging (MALDI­MSI) es un método de imagen química que puede visualizar distribuciones espaciales de moléculas particulares. Hasta ahora, las imágenes de tejido vegetal han utilizado principalmente la criosección, lo cual puede ser poco práctico para la preparación de muestras de imágenes con áreas grandes, tales como los pétalos completos de una flor. La obtención de imágenes de tejido vegetal no seccionado presenta sus propias dificultades durante la extracción de metabolitos a la superficie, debido a la cutícula cerosa de la planta. Métodos: Abordamos esto usando técnicas establecidas de deslipidación combinados con una extracción de vapor por solvente antes de aplicar por aspersión la matriz en bajas concentraciones. Resultados: Usando este procedimiento, obtuvimos imágenes de tejido de tres especies de plantas diferentes (dos flores y una hoja de planta carnívora). Análisis de factorización material de los datos obtenidos revelaron una amplia gama de pequeñas moléculas específicas en plantas con diversos grados de localización en porciones específicas de las muestras de tejido, al igual que facilitó la detección y remoción de las señales de fondo. Conclusión: Nuestro trabajo demuestra la aplicabilidad de MALDI­MSI hacía muestras de plantas secadas a presión sin congelación o criosección, creando el marco para la identificación de moléculas resueltas espacialmente. Aumento de la resolución de masas e inclusión de la espectrometría de masas en tándem son pasos necesarios para obtener identificación de compuestos más específica y confiable.

End binding-3 inhibitor activates regenerative program in age-related macular degeneration.

Wet age-related macular degeneration (AMD), characterized by leaky neovessels emanating from the choroid, is a main cause of blindness. As current treatments for wet AMD require regular intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics, there is a need for the development of less invasive treatments. Here, we designed an allosteric inhibitor of end binding-3 (EB3) protein, termed EBIN, which reduces the effects of environmental stresses on endothelial cells by limiting pathological calcium signaling. Delivery of EBIN via eye drops in mouse and non-human primate (NHP) models of wet AMD prevents both neovascular leakage and choroidal neovascularization. EBIN reverses the epigenetic changes induced by environmental stresses, allowing an activation of a regenerative program within metabolic-active endothelial cells comprising choroidal neovascularization (CNV) lesions. These results suggest the therapeutic potential of EBIN in preventing the degenerative processes underlying wet AMD.

Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway.

Fragile X messenger ribonucleoprotein 1 protein (FMRP) binds many mRNA targets in the brain. The contribution of these targets to fragile X syndrome (FXS) and related autism spectrum disorder (ASD) remains unclear. Here, we show that FMRP deficiency leads to elevated microtubule-associated protein 1B (MAP1B) in developing human and non-human primate cortical neurons. Targeted MAP1B gene activation in healthy human neurons or MAP1B gene triplication in ASD patient-derived neurons inhibit morphological and physiological maturation. Activation of Map1b in adult male mouse prefrontal cortex excitatory neurons impairs social behaviors. We show that elevated MAP1B sequesters components of autophagy and reduces autophagosome formation. Both MAP1B knockdown and autophagy activation rescue deficits of both ASD and FXS patients' neurons and FMRP-deficient neurons in ex vivo human brain tissue. Our study demonstrates conserved FMRP regulation of MAP1B in primate neurons and establishes a causal link between MAP1B elevation and deficits of FXS and ASD.

Recumbent Ergometer vs Treadmill Cardiopulmonary Exercise Test in HFpEF: Implications for Chronotropic Response and Exercise Capacity.

BACKGROUND: Cardiopulmonary exercise testing (CPET) can identify mechanisms of exercise intolerance in heart failure with preserved ejection fraction (HFpEF), but exercise modalities with differing body positions (eg, recumbent ergometer, treadmill) are broadly used. In this study, we aimed to determine whether body position affects CPET parameters in patients with HFpEF. METHODS: Subjects with stable HFpEF (n = 23) underwent noninvasive treadmill CPET, followed by an invasive recumbent-cycle ergometer CPET within 3 months. A comparison group undergoing similar studies included healthy subjects (n = 5) and subjects with pulmonary arterial hypertension (n = 6). RESULTS: The peak oxygen consumption (VO2peak) and peak heart rate were significantly lower in the recumbent vs the upright position (10.1 vs 13.1 mL/kg/min [Δ-3 mL/kg/min]; P < 0.001; and 95 vs 113 bpm [Δ-18 bpm]; P < 0.001, respectively). No significant differences were found in the minute ventilation to carbon dioxide production ratio, end-tidal pressure of carbon dioxide or respiratory exchange ratio. A similar pattern was observed in the comparison groups. CONCLUSIONS: Compared to recumbent ergometer, treadmill CPET revealed higher VO2peak and peak heart rate response. When determining chronotropic incompetence to adjust beta-blocker administration in HFpEF, body position should be taken into account.

Coronary Vasospasm Causing Chest Pain in Early Postoperative Heart Transplantation.

Coronary vasospasm is a rare complication after heart transplant. Due to denervation of the donor heart, patients are typically asymptomatic but may present with cardiac arrhythmias or cardiac arrest. We present a patient with a recent heart transplant who experienced chest pain and was found to have coronary vasospasm.

FXR1 regulation of parvalbumin interneurons in the prefrontal cortex is critical for schizophrenia-like behaviors.

Parvalbumin interneurons (PVIs) are affected in many psychiatric disorders including schizophrenia (SCZ), however the mechanism remains unclear. FXR1, a high confident risk gene for SCZ, is indispensable but its role in the brain is largely unknown. We show that deleting FXR1 from PVIs of medial prefrontal cortex (mPFC) leads to reduced PVI excitability, impaired mPFC gamma oscillation, and SCZ-like behaviors. PVI-specific translational profiling reveals that FXR1 regulates the expression of Cacna1h/Cav3.2 a T-type calcium channel implicated in autism and epilepsy. Inhibition of Cav3.2 in PVIs of mPFC phenocopies whereas elevation of Cav3.2 in PVIs of mPFC rescues behavioral deficits resulted from FXR1 deficiency. Stimulation of PVIs using a gamma oscillation-enhancing light flicker rescues behavioral abnormalities caused by FXR1 deficiency in PVIs. This work unveils the function of a newly identified SCZ risk gene in SCZ-relevant neurons and identifies a therapeutic target and a potential noninvasive treatment for psychiatric disorders.

Technical and clinical study of x-ray-based surface echo probe tracking using an attached fiducial apparatus.

PURPOSE: Several types of structural heart intervention (SHI) use information from multiple imaging modalities to complete an interventional task. For example, in transcatheter aortic valve replacement (TAVR), placement and deployment of a bioprosthetic aortic valve in the aorta is primarily guided by x-ray fluoroscopy (XRF), and echocardiography provides visualization of cardiac anatomy and blood flow. However, simultaneous interpretation of independent x-ray and echo displays remains a challenge for the interventionalist. The purpose of this work was to develop a novel echo/x-ray co-registration solution in which volumetric transthoracic echo (TTE) is transformed to the x-ray coordinate system by tracking the three-dimensional (3D) pose of a probe fiducial attachment from its appearance in two-dimensional (2D) x-ray images. METHODS: A fiducial attachment for a commercial TTE probe consisting of rings of high-contrast ball bearings was designed and fabricated. The 3D pose (position and orientation) of the fiducial attachment is estimated from a 2D x-ray image using an algorithm in which a virtual point cloud model of the attachment is iteratively rotated, translated, and forward-projected onto the image until the average sum-of-squares of grayscale values at the projected points is minimized. Fiducial registration error (FRE) and target registration error (TRE) of this approach were evaluated in phantom studies using TAVR-relevant gantry orientations and four standard acoustic windows for the TTE probe. A patient study was conducted to assess the clinical suitability of the fiducial attachment prototype during TTE imaging of patients undergoing SHI. TTE image quality for the task of guiding a transcatheter procedure was evaluated in a reviewer study. RESULTS: The 3D FRE ranged from 0.32 ± 0.03 mm (mean ± SD) to 1.31 ± 0.05 mm, depending on C-arm orientation and probe acoustic window. The 3D TRE ranged from 1.06 ± 0.03 mm to 2.42 ± 0.06 mm. Fiducial pose estimation was stable when >75% of the fiducial markers were visible in the x-ray image. A panel of reviewers graded the presentation of heart valves in TTE images from 48 SHI patients. While valve presentation did not differ significantly between acoustic windows (P > 0.05), the mitral valve did achieve a significantly higher image quality compared to the aortic and tricuspid valves (P < 0.001). Overall, reviewers perceived sufficient image quality in 76.5% of images of the mitral valve, 54.9% of images of the aortic valve, and 48.6% of images of the tricuspid valve. CONCLUSIONS: Fiducial-based tracking of a commercial TTE probe is compatible with clinical SHI workflows and yields 3D target registration error of less than 2.5 mm for a variety of x-ray gantry geometries and echo probe acoustic windows. Although TTE image quality with respect to target valve anatomy was sufficient for the majority of cases examined, prescreening of patients for sufficient TTE quality would be helpful.

It hurts to swallow! Pseudoachalasia resulting from attempted transcatheter occlusion of a giant congenital coronary artery fistula.

Congenital coronary artery fistula (CAF) is a rare anomaly that can cause heart failure and myocardial ischemia. In recent decades, transcatheter approaches to occlude CAF have emerged as minimally invasive alternatives to surgical ligation. Reported complications with transcatheter CAF occlusion include device embolization and dissection. We report the first case of attempted transcatheter occlusion of a giant CAF that resulted in severe pseudoachalasia.

VE-PTP stabilizes VE-cadherin junctions and the endothelial barrier via a phosphatase-independent mechanism.

Vascular endothelial (VE) protein tyrosine phosphatase (PTP) is an endothelial-specific phosphatase that stabilizes VE-cadherin junctions. Although studies have focused on the role of VE-PTP in dephosphorylating VE-cadherin in the activated endothelium, little is known of VE-PTP's role in the quiescent endothelial monolayer. Here, we used the photoconvertible fluorescent protein VE-cadherin-Dendra2 to monitor VE-cadherin dynamics at adherens junctions (AJs) in confluent endothelial monolayers. We discovered that VE-PTP stabilizes VE-cadherin junctions by reducing the rate of VE-cadherin internalization independently of its phosphatase activity. VE-PTP serves as an adaptor protein that through binding and inhibiting the RhoGEF GEF-H1 modulates RhoA activity and tension across VE-cadherin junctions. Overexpression of the VE-PTP cytosolic domain mutant interacting with GEF-H1 in VE-PTP-depleted endothelial cells reduced GEF-H1 activity and restored VE-cadherin dynamics at AJs. Thus, VE-PTP stabilizes VE-cadherin junctions and restricts endothelial permeability by inhibiting GEF-H1, thereby limiting RhoA signaling at AJs and reducing the VE-cadherin internalization rate.

Differential Expression of PU.1 and Key T Lineage Transcription Factors Distinguishes Fetal and Adult T Cell Development.

The PU.1 transcription factor plays a critical role in the regulation of T cell development, so a report that it is dispensable for fetal thymopoiesis is puzzling. To understand this paradox, we examined the requirement for PU.1, encoded by Spi1, during fetal, neonatal, and adult thymopoiesis in a PU.1 hypomorphic mouse generated by deletion of the Spi1 14-kb upstream regulatory element and by analysis of patterns of gene expression in fetal and adult T cell progenitors. Our data demonstrate that the initiation of thymopoiesis during early gestation is less dependent on PU.1 compared with T cell differentiation in adults and that fetal T cell progenitors express lower levels of Spi1 compared with their adult counterparts. We also show that expression of the core network of T lineage transcription factors regulated by PU.1 differs in fetal and adult T cell progenitors. In particular, PU.1-regulated genes that promote T cell differentiation are differentially expressed in fetal versus adult early T lineage progenitors. These results indicate that the transcriptional differences between the fetal and adult T cell developmental programs are driven in part by differential levels of PU.1 expression and that this likely underlies the differences in the properties of fetal and adult T cell progenitors.

A multi-scale model for hair follicles reveals heterogeneous domains driving rapid spatiotemporal hair growth patterning.

The control principles behind robust cyclic regeneration of hair follicles (HFs) remain unclear. Using multi-scale modeling, we show that coupling inhibitors and activators with physical growth of HFs is sufficient to drive periodicity and excitability of hair regeneration. Model simulations and experimental data reveal that mouse skin behaves as a heterogeneous regenerative field, composed of anatomical domains where HFs have distinct cycling dynamics. Interactions between fast-cycling chin and ventral HFs and slow-cycling dorsal HFs produce bilaterally symmetric patterns. Ear skin behaves as a hyper-refractory domain with HFs in extended rest phase. Such hyper-refractivity relates to high levels of BMP ligands and WNT antagonists, in part expressed by ear-specific cartilage and muscle. Hair growth stops at the boundaries with hyper-refractory ears and anatomically discontinuous eyelids, generating wave-breaking effects. We posit that similar mechanisms for coupled regeneration with dominant activator, hyper-refractory, and wave-breaker regions can operate in other actively renewing organs.

Inertial sensing algorithms for long-term foot angle monitoring for assessment of idiopathic toe-walking.

When children walk on their toes for no known reason, the condition is called Idiopathic Toe Walking (ITW). Assessing the true severity of ITW can be difficult because children can alter their gait while under observation in clinic. The ability to monitor the foot angle during daily life outside of clinic may improve the assessment of ITW. A foot-worn, battery-powered inertial sensing device has been designed to monitor patients' foot angle during daily activities. The monitor includes a 3-axis accelerometer, 2-axis gyroscope, and a low-power microcontroller. The device is necessarily small, with limited battery capacity and processing power. Therefore a high-accuracy but low-complexity inertial sensing algorithm is needed. This paper compares several low-complexity algorithms' aptitude for foot-angle measurement: accelerometer-only measurement, finite impulse response (FIR) and infinite impulse response (IIR) complementary filtering, and a new dynamic predict-correct style algorithm developed using fuzzy c-means clustering. A total of 11 subjects each walked 20 m with the inertial sensing device fixed to one foot; 10 m with normal gait and 10 m simulating toe walking. A cross-validation scheme was used to obtain a low-bias estimate of each algorithm's angle measurement accuracy. The new predict-correct algorithm achieved the lowest angle measurement error: <5° mean error during normal and toe walking. The IIR complementary filtering algorithm achieved almost-as good accuracy with less computational complexity. These two algorithms seem to have good aptitude for the foot-angle measurement problem, and would be good candidates for use in a long-term monitoring device for toe-walking assessment.