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Although colorectal cancer (CRC) remains the second leading cause of cancer-related death in the United States, the overall incidence and mortality from the disease have declined in recent decades. In contrast, there has been a steady increase in the incidence of CRC in individuals under 50 years of age. Hereditary syndromes contribute disproportionately to early onset CRC (EOCRC). These include microsatellite instability high (MSI+) tumors arising in patients with Lynch Syndrome. However, most EOCRCs are not associated with familial syndromes or MSI+ genotypes. Comprehensive genomic profiling has provided the basis of improved more personalized treatments for older CRC patients. However, less is known about the basis of sporadic EOCRC. To define the genomic landscape of EOCRC we used DNA content flow sorting to isolate diploid and aneuploid tumor fractions from 21 non-hereditary cases. We then generated whole exome mutational profiles for each case and whole genome copy number, telomere length, and EGFR immunohistochemistry (IHC) analyses on subsets of samples. These results discriminate the molecular features of diploid and aneuploid EOCRC and provide a basis for larger population-based studies and the development of effective strategies to monitor and treat this emerging disease.

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INTRODUCTION: Low back pain has become a substantial health problem in all developed countries. Many healthcare professionals and content creators have begun sharing their treatment methods and opinions through social media, especially the video-based platform TikTok. TikTok has been downloaded more than 2.6 billion times with over a billion daily users. Its influence on public health makes it imperative that information be accurate and safe. This study aims to analyze TikTok's most popular content on lower back pain and how orthopaedic surgeons contribute on this growing platform. OBJECTIVES: To analyze TikTok's most popular content on lower back pain and how orthopaedic surgeons are and can contribute on this growing platform. METHODS: A TikTok search conducted on April 22, 2023, using the terms '#lowerbackpain'and '#lowbackpainrelief,' resulted in numerous videos, 100 of which met inclusion criteria. Videos were included if they were related to the content, had more than 1000 views, were in English, and were not duplicates. Video characteristics were recorded and evaluated for quality by two reviewers using DISCERN. A two-sample t-test was used to assess differences. RESULTS: Overall, the top videos on lower back pain had an average of 2,061,396 views, with a mean DISCERN score of 34. The mean total DISCERN score was 36 and 34 for physicians and nonphysicians, respectively, while the video by the orthopaedic surgeon (n = 1) scored 31. The most recommended treatments included at-home exercises (n = 75) and visiting a chiropractor (n = 4). CONCLUSION: We find that the information presented by nonphysicians offered quick, at-home fixes to medical problems without offering any research or proven data to support their claims. We cannot overlook Tiktok's immense influence in the realm of orthopaedic health as it has become a sphere of information dissemination and education. Thus, we suggest that there is not necessarily a need for a greater number of surgeons and/or resident physicians to involve themselves on the platform, but rather the involvement of governing bodies and spine societies to put out position statements for our patients.

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Primary intracranial gliomas are a heterogeneous class of lesions that rarely metastasize. Even more infrequently, they may spread caudally into the spinal cord causing spinal gliomatosis. In this case, we discuss an 18-year-old male patient with a diagnosis of grade IV astrocytoma with spinal gliomatosis, specifically detailing the radiographic progression of the disease over 38 months. We also discuss the significance of the change in the WHO classification of central nervous system tumors, as this patient's survival duration is inconsistent with the low survival rates expected of glioblastoma, and rather more consistent with a grade IV astrocytoma.

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The mechanistic target of rapamycin (mTOR) pathway is a signaling system integral to neural growth and migration. In both patients and rodent models, mutations to the phosphatase and tensin homolog gene (PTEN) on chromosome 10 results in hyperactivation of the mTOR pathway, as well as seizures, intellectual disabilities and autistic behaviors. Rapamycin, an inhibitor of mTOR, can reverse the epileptic phenotype of neural subset specific Pten knockout (NS-Pten KO) mice, but its impact on behavior is not known. To determine the behavioral effects of rapamycin, male and female NS-Pten KO and wildtype (WT) mice were assigned as controls or administered 10 mg/kg of rapamycin for 2 weeks followed by behavioral testing. Rapamycin improved social behavior in both genotypes and stereotypic behaviors in NS-Pten KO mice. Rapamycin treatment resulted in a reduction of several measures of activity in the open field test in both genotypes. Rapamycin did not reverse the reduced anxiety behavior in KO mice. These data show the potential clinical use of mTOR inhibitors by showing its administration can reduce the production of autistic-like behaviors in NS-Pten KO mice.

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Lateral patellar dislocations often occur in a young, athletic population of recurrent dislocators with generalized laxity and an interest in returning to an active lifestyle. A recent appreciation for the distal patellotibial complex has directed surgeons toward attempting to re-create the native anatomy and knee biomechanics during medial patellar reconstructive procedures. By reconstructing the medial patellotibial ligament (MPTL) in addition to the medial patella-femoral ligament (MPFL) and medial quadriceps tendon-femoral ligament (MQTFL), the current article describes a potentially more stable construct that can be utilized in patients with subluxation with the knee in full extension, patellar instability with the knee in deep flexion, genu recurvatum, and generalized hyperlaxity. Additionally, the current technique utilizes a tibialis anterior allograft. The purpose of this Technical Note is to describe, in detail, the current authors' technique for a combined MPFL, MQTFL, and MPTL reconstruction.

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BACKGROUND: Pediatric spinal arteriovenous shunts (SAVS) are rare lesions with heterogeneous pathogenesis and clinical manifestations. OBJECTIVE: To evaluate the clinical characteristics, angioarchitecture, and technical/clinical outcomes in SAVS through a large single-center cohort analysis and meta-analysis of individual patient data. METHODS: A retrospective institutional database identified children (aged 0-21 years) who underwent digital subtraction spinal angiography (DSA) for SAVS between January 1996 and July 2021. Clinical data were recorded to evaluate angioarchitecture, generate modified Aminoff-Logue gait disturbance scores (AL) and McCormick grades (MC), and assess outcomes. We then performed a systematic literature review following PRISMA-IPD (Preferred Reporting Items for Systematic Reviews and Meta-Analyses for individual patient data) guidelines, extracting similar data on individual patients for meta-analysis. RESULTS: The cohort consisted of 28 children (M:F=11:17) with 32 SAVS lesions, with a mean age of 12.8±1.1 years at diagnosis. At presentation, SAVS were most highly concentrated in the cervical region (40.6%). Children had a median AL=2 and MC=2, with thoracolumbar AVS carrying the greatest disability. Among treated cases, complete obliteration was achieved in 48% of cases and median AL scores and MC grades both improved by one point. Systematic literature review identified 161 children (M:F=96:65) with 166 SAVS lesions with a mean age of 8.7±0.4 years. Among studies describing symptom chronicity, 37/51 (72.5%) of children presented acutely. At presentation, children had a median AL=4 and MC=3, with thoracolumbar AVS carrying the highest MC grades. After intervention, median AL and MC both improved by one point. CONCLUSIONS: This study provides epidemiologic information on the location, onset, and presentation of the full spectrum of pediatric SAVS, highlighting the role of targeted treatment of high-risk features.

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BACKGROUND: Individuals on immunosuppressive therapies experience greater morbidity and mortality due to vaccine-preventable illnesses, but there are low rates of adherence to immunization guidelines within this population. OBJECTIVE: To determine the effectiveness of clinician-led education, patient-centered dialogue, and immediately available immunization on influenza vaccination uptake in patients taking immunosuppressive therapies. METHOD: We used a controlled before-and-after quasi-experimental design to evaluate our quality improvement intervention occurring from September 2019 to March 2020, with follow-up through July 2020. The study included 2 dermatology practices wherein nursing staff offered influenza vaccination during patient rooming (standard care). Within each practice, clinicians either implemented the intervention or provided only standard care. Patients received the intervention or standard care depending on the clinician they visited. Patients seen at the 2 clinics during the intervention period were included in analyses if they were taking or newly prescribed immunosuppressant medication at the time of their visit. We examined influenza immunization status for 3 flu seasons: 2017-2018 (preintervention), 2018-2019 (preintervention), and 2019-2020 (intervention). INTERVENTION: Immunosuppressed patients initially declining an influenza vaccine were provided dermatologist-led education on the benefits of immunization. Dermatologists explored and addressed individual patients' immunization concerns. Influenza vaccination was then offered immediately postdialogue. RESULTS: Analyses included 201 dermatology patients who were prescribed or currently taking immunosuppressive medication (intervention group [72.6%], comparison group [27.4%]). During the intervention period, 91.1% of the intervention group received influenza vaccination compared to 56.4% of the comparison group. Vaccination trends from 2018-2019 (preintervention) to 2019-2020 (intervention) differed significantly between groups (χ2 = 22.92, P < .001), with greater improvement in the intervention group. In 2019-2020, influenza vaccination was more likely in the intervention group relative to the comparison group (odds ratio: 16.22, 95% confidence interval: 5.55-47.38). In the subset of patients that had never received an influenza vaccine, influenza immunization in 2019-2020 was more common in the intervention group (75.8%, 25/33) relative to the comparison group (13.3%, 2/15, P < .001). CONCLUSION: The intervention successfully addressed vaccine hesitancy and improved influenza immunization rates in an immunosuppressed population receiving care from a specialty clinic. Implementing a similar model across specialty clinics may improve vaccination rates for influenza, coronavirus disease 2019, and other vaccine-preventable illnesses in other populations.

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New imaging and biomechanical approaches have heralded a renaissance in our understanding of crocodylian anatomy. Here, we review a series of approaches in the preparation, imaging, and functional analysis of the jaw muscles of crocodylians. Iodine-contrast microCT approaches are enabling new insights into the anatomy of muscles, nerves, and other soft tissues of embryonic as well as adult specimens of alligators. These imaging data and other muscle modeling methods offer increased accuracy of muscle sizes and attachments without destructive methods like dissection. 3D modeling approaches and imaging data together now enable us to see and reconstruct 3D muscle architecture which then allows us to estimate 3D muscle resultants, but also measurements of pennation in ways not seen before. These methods have already revealed new information on the ontogeny, diversity, and function of jaw muscles and the heads of alligators and other crocodylians. Such approaches will lead to enhanced and accurate analyses of form, function, and evolution of crocodylians, their fossil ancestors and vertebrates in general.

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Pseudolipomas are an uncommon clinical manifestation appearing as a non-encapsulated prominence of subcutaneous fat on MRI. Post-traumatic pseudolipomas (PTLs) are thought to arise from neoadipogenesis following acute or chronic trauma. These are most commonly located on the lower extremities, gluteal, and trochanteric regions. Here, we report a case of PTL in a high school athlete, arising in the posterior neck after weight training with performing barbell squats without neck padding. To our knowledge, this case represents a novel association between PTLs and weight training exercises.

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PURPOSE: Intrinsic foot muscles maintain foot structural integrity and contribute to functional movement, posture and balance. Thus, assessing intrinsic foot muscle size and strength are important. Magnetic resonance imaging (MRI) has been shown to accurately image the individual muscles but is costly and time consuming. Ultrasound (US) imaging may provide an alternative that is less costly and more readily available. The purpose of this study was to investigate the validity and intratester reliability of US imaging in measuring intrinsic foot muscle size in comparison to MRI. METHODS: US and MRI were employed to measure the intrinsic foot muscle size involving 35 participants (females = 13; males = 22). The scanned intrinsic foot muscles included the flexor hallucis brevis (FHB), abductor hallucis (ABDH), flexor digitorum brevis (FDB), quadratus plantae (QP) and abductor digiti minimi (ADM). Pearson product correlation (r), intraclass correlation coefficients (ICC), standard error of the measurement (SEm) and minimal detectable difference (MDD) were calculated. RESULTS: High correlations were detected between the US and MRI cross-sectional area (CSA) measurements (r = .971 to 0.995). Test reliability was excellent for both MRI and US (ICC = 0.994 to 0.999). Limits of agreement between MRI and US measurements from ranged from 5.7 to 12.2% of muscle size. SEm values for US ranged from 0.026 to 0.044 cm2, while the SEm for MRI ranged from 0.018 to 0.023 cm2. MDD values for US ranged from 0.073 to 0.122 cm2, while MRI ranged from 0.045 to 0.064 cm2. CONCLUSIONS: US appears to be a valid and reliable alternative to MRI when measuring intrinsic foot muscle CSA. While US is less costly and more readily available, the MRI results were shown to be slightly more precise.

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Preventable healthcare-associated harm results in significant morbidity and mortality in the United States, costing nearly 400 000 patient lives annually. The Institute for Healthcare Improvement provides high-quality educational resources tailored for working healthcare professionals. One such resource is the Certified Professional in Patient Safety (CPPS™) review course, which equips professionals with advanced proficiency in 5 core patient safety domains. The CPPS™ certification is the only interprofessional, patient safety science credential recognized worldwide. In 2010, the Lucian Leape Institute at the National Patient Safety Foundation described the critical need for medical students to participate in patient safety solutions as well. However, equivalent patient safety credentialing remains challenging for students in the preclinical and clinical stages of training to obtain. To address this growing dilemma, the Texas College of Osteopathic Medicine (TCOM) piloted the first-of-its-kind CPPS™ course with 10 medical students to test a novel, academic-level approach to patient safety curriculum. Medical students showed large gains in performance on the post-test (83.18% ± 26.12%) compared to the pre-test (46.46% ± 27.18%) (P < .001, η2 p = .368), representing increased knowledge across all learning domains. On the national certification examination, students had a 90% first-time pass rate, exceeding the current national average of 70% for first-time examinees. In satisfaction surveys, students expressed the value of pilot curriculum for their medical training, the importance of similar Patient Safety Education and CPPS certification for all medical students, their confidence as future healthcare change agents. Content analysis of open response questions revealed 3 key areas of strength and opportunity for guiding future iterations of the course. This pilot generates a future vision of patient safety, equipping students with critical knowledge to systematically improve healthcare quality.

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Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.

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BACKGROUND: Heart rate-corrected QT interval (QTc) prolongation, whether secondary to drugs, genetics including congenital long QT syndrome, and/or systemic diseases including SARS-CoV-2-mediated coronavirus disease 2019 (COVID-19), can predispose to ventricular arrhythmias and sudden cardiac death. Currently, QTc assessment and monitoring relies largely on 12-lead electrocardiography. As such, we sought to train and validate an artificial intelligence (AI)-enabled 12-lead ECG algorithm to determine the QTc, and then prospectively test this algorithm on tracings acquired from a mobile ECG (mECG) device in a population enriched for repolarization abnormalities. METHODS: Using >1.6 million 12-lead ECGs from 538 200 patients, a deep neural network (DNN) was derived (patients for training, n = 250 767; patients for testing, n = 107 920) and validated (n = 179 513 patients) to predict the QTc using cardiologist-overread QTc values as the "gold standard". The ability of this DNN to detect clinically-relevant QTc prolongation (eg, QTc ≥500 ms) was then tested prospectively on 686 patients with genetic heart disease (50% with long QT syndrome) with QTc values obtained from both a 12-lead ECG and a prototype mECG device equivalent to the commercially-available AliveCor KardiaMobile 6L. RESULTS: In the validation sample, strong agreement was observed between human over-read and DNN-predicted QTc values (-1.76±23.14 ms). Similarly, within the prospective, genetic heart disease-enriched dataset, the difference between DNN-predicted QTc values derived from mECG tracings and those annotated from 12-lead ECGs by a QT expert (-0.45±24.73 ms) and a commercial core ECG laboratory [10.52±25.64 ms] was nominal. When applied to mECG tracings, the DNN's ability to detect a QTc value ≥500 ms yielded an area under the curve, sensitivity, and specificity of 0.97, 80.0%, and 94.4%, respectively. CONCLUSIONS: Using smartphone-enabled electrodes, an AI DNN can predict accurately the QTc of a standard 12-lead ECG. QTc estimation from an AI-enabled mECG device may provide a cost-effective means of screening for both acquired and congenital long QT syndrome in a variety of clinical settings where standard 12-lead electrocardiography is not accessible or cost-effective.

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OBJECTIVE: Focal cortical dysplasia (FCD) accounts for nearly half of all cases of medically refractory epilepsy in the pediatric and adult patient populations. This neurological disorder stems from localized malformations in cortical brain tissue due to impaired neuronal proliferation, differentiation, and migration patterns. Recent studies in animal models have highlighted the potential role of the Fragile X mental retardation protein (FMRP) levels in FCD. The purpose of this study was to investigate the status of FMRP activation in cortical brain tissues surgically resected from patients with FCD. In parallel, this study also investigated protein levels within the PI3K/AKT/mTOR and canonical Wnt signaling pathways. METHODS: Pathologic tissue from malformative lesions of FCD patients with medically refractory epilepsy was compared to relatively normal control non-epileptic tissue from patients with intracranial neoplasms. A series of western blotting assays were performed to assess key proteins in the PI3K/AKT/mTOR, canonical Wnt signaling pathways, and FMRP. RESULTS: There was suppression of S235/236-phosphorylated S6, GSK3α, and GSK3ß protein levels in samples derived from FCD patients, compared to non-epileptic controls. FCD samples also had significantly greater levels of total and S499-phosphorylated FMRP. CONCLUSION: These findings support our hypothesis that malformative lesions associated with FCD are characterized by high levels of FMRP activation along with dysregulation of both PI3K/AKT/mTOR and canonical Wnt signaling. These novel clinical findings extend previous work in animal models, further suggesting a potential unforeseen role of GSK3α and GSK3ß in the pathophysiology of FCD and refractory epilepsy.

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Chronic, non-surgical, non-specific anterior knee pain is a common source of functionally limiting chronic ailment, especially in a young athletic and active-duty military population. The infrapatellar branch of the saphenous is becoming a common therapeutic target for the diagnosis and treatment of anterior knee pain. It is a nerve commonly injured during knee surgeries and trauma, resulting in neuroma formation and chronic neuropathic pain states, and it can also transmit nociceptive input from patients with non-surgical anterior knee pain of multiple etiologies. Several methods have been employed to treat this condition. After the diagnosis of infrapatellar saphenous neuralgia, the nerve is safely ablated using radiofrequency ablation, neurolytic solutions, and, most recently, cryoablation using the handheld iovera® cryoablation system (Myoscience, Inc. Fremont, CA). Cryoablation is an attractive technique because it is minimally invasive, not permanent, and well tolerated by the patient with only local anesthesia. We have previously described a technique using a non-invasive peripheral nerve stimulator to identify and treat the exact location of the nerve more precisely, thereby optimizing treatment success and procedural simplicity. This case series illustrates our initial use and success with this technique. Further follow-up and randomized sham-controlled trials are also planned.

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Fragile X syndrome (FXS) is a genetic disorder caused by a trinucleotide (CGG) expansion mutation in the Fmr1 gene located on the X chromosome. It is characterized by hyperactivity, increased anxiety, repetitive-stereotyped behaviors, and impaired language development. Many children diagnosed with FXS also experience seizures during their lifetime. However, the underlying etiology of the relationship between FXS and epilepsy is not fully understood. Ultrasonic vocalizations (UVs) are one tool that may be used to measure early behavioral changes in mouse pups. In the present study, neonatal UVs were analyzed as a measure of communicative behavior in a mouse model of FXS, both with and without early-life seizures (ELSs). On postnatal day (PD) 10, status epilepticus (SE) was induced via intraperitoneal injections of 0.5% kainic acid (2.0 mg/kg) in male Fmr1 knockout (KO) and wild-type (WT) mice. On PD 12, all pups were temporarily isolated from their dam and UVs were recorded. Significant alterations were found in both spectral and temporal measures across genotype and seizure groups. Early-life seizure experience resulted in a significant increase in the quantity of UVs only in WT animals (p < 0.05). We also found that while there was no difference between genotypes in the total number of vocalizations made, calls produced by Fmr1 KO mice were significantly shorter and had a higher peak frequency compared with WT mice. Overall, these findings support the use of vocalization behavior as an early phenotypic marker and highlight the importance of utilizing double-hit models to better understand comorbid disorders.

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Metformin is the safest and the most widely prescribed first-line therapy for managing hyperglycemia due to different underlying causes, primarily type 2 diabetes mellitus. In addition to its euglycemic properties, metformin has stimulated a wave of clinical trials to investigate benefits on aging-related diseases and longevity. Such an impact on the lifespan extension would undoubtedly expand the therapeutic utility of metformin regardless of glycemic status. However, there is a scarcity of studies evaluating whether metformin has differential cognitive effects across age, sex, glycemic status, metformin dose, and duration of metformin treatment and associated pathological conditions. By scrutinizing the available literature on animal and human studies for metformin and brain function, we expect to shed light on the potential impact of metformin on cognition across age, sex, and pathological conditions. This review aims to provide readers with a broader insight of (a) how metformin differentially affects cognition and (b) why there is a need for more translational and clinical studies examining multifactorial interactions. The outcomes of such comprehensive studies will streamline precision medicine practices, avoiding "fit for all" approach, and optimizing metformin use for longevity benefit irrespective of hyperglycemia.

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Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability and a significant genetic contributor to Autism spectrum disorder. In addition to autistic-like phenotypes, individuals with FXS are subject to developing numerous comorbidities, one of the most prevalent being seizures. In the present study, we investigated how a single early-life seizure superimposed on a genetic condition impacts the autistic-like behavioral phenotype of the mouse. We induced status epilepticus (SE) on postnatal day (PD) 10 in Fmr1 wild type (WT) and knockout (KO) mice. We then tested the mice in a battery of behavioral tests during adulthood (PD90) to examine the long-term impact of an early-life seizure. Our findings replicated prior work that reported a single instance of SE results in behavioral deficits, including increases in repetitive behavior, enhanced hippocampal-dependent learning, and reduced sociability and prepulse inhibition (p <  0.05). We also observed genotypic differences characteristic of the FXS phenotype in Fmr1 KO mice, such as enhanced prepulse inhibition and repetitive behavior, hyperactivity, and reduced startle responses (p <  0.05). Superimposing a seizure on deletion of Fmr1 significantly impacted repetitive behavior in a nosepoke task. Specifically, a single early-life seizure increased consecutive nose poking behavior in the task in WT mice (p <  0.05), yet seizures did not exacerbate the elevated stereotypy observed in Fmr1 KO mice (p >  0.05). Overall, these findings help to elucidate how seizures in a critical period of development can impact long-term behavioral manifestations caused by underlying gene mutations in Fmr1. Utilizing double-hit models, such as superimposing seizures on the Fmr1 mutation, can help to enhance our understanding of comorbidities in disease models.

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There is increasing evidence that seizures during early development can impact ultrasonic vocalizations (USVs) emitted from neonatal mice. However, most of the effects of early-life seizures have been reported using chemoconvulsants that produce continuous seizures (status epilepticus). In the present study, we evaluated the impact of different seizure frequency loads during early-life vocalization development in C57BL/6J male and female mice. For the high seizure load (HSL) paradigm, we administered 3 flurothyl seizures to mice on postnatal day (PD) 7 through PD11, and recorded USVs on PD12. We found that the induction of seizures across PD7-11 resulted in increased average duration (P < 0.05) and cumulative duration (P < 0.05) of USVs across both sexes. Call-type analyses indicated several call-type changes, including reduced production of complex call-types from males' HSL condition. For the low seizure load (LSL) paradigm, we induced 3 flurothyl seizures only on PD10 and recorded USVs on PD12. We found no change in any spectral or temporal features of USVs. However, call-type production analyses indicated that both male and female animals from the LSL paradigm also produced changes in call-types. This study provides evidence that the magnitude of communication impairment following seizures is significantly impacted by seizure frequency load early in development.

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