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War-related medical costs for U.S. veterans of Iraq and Afghanistan may be enormous because of differences between these wars and previous conflicts: (1) Many veterans survive injuries that would have killed them in past wars, and (2) improvised explosive device attacks have caused "polytraumatic" injuries (multiple amputations; brain injury; severe facial trauma or blindness) that require decades of costly rehabilitation. In 2035, today's veterans will be middle-aged, with health issues like those seen in aging Vietnam veterans, complicated by comorbidities of posttraumatic stress disorder, traumatic brain injury, and polytrauma. This article cites emerging knowledge about best practices that have demonstrated cost-effectiveness in mitigating the medical costs of war. We propose that clinicians employ early interventions (trauma care, physical therapy, early post-traumatic stress disorder diagnosis) and preventive health programs (smoking cessation, alcohol-abuse counseling, weight control, stress reduction) to treat primary medical conditions now so that we can avoid treating costly secondary and tertiary complications in 2035. (We should help an amputee reduce his cholesterol and maintain his weight at age 30, rather than treating his heart disease or diabetes at age 50.) Appropriate early interventions for primary illness should preserve veterans' functional status, ensure quality clinical care, and reduce the potentially enormous cost burden of their future health care. [ABSTRACT FROM AUTHOR]

Patients with major injuries to the upper limbs sometimes fail to achieve successful limb salvage. During the attempt to fashion a functional limb, multiple painful procedures may be ventured. Despite the best efforts of surgeons and therapists, a nonfunctioning or painful upper limb may remain in place for many months or years before late delayed amputation and progression to productive rehabilitation occur. We present three patient cases that illustrate failed upper-limb salvage. In each case, patients expressed a desire for amputation at 6 months after their injury. To reduce the pain and suffering that patients with failed limb salvage endure, we propose a paradigm shift in the limb-salvage time line. We suggest that patients be evaluated for early delayed amputation 6 months after their injury. [ABSTRACT FROM AUTHOR]

Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a novel and selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated cytotoxic T cells. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC.

Purpose of Review: The integration of digital technology into medical practice is often thrust upon clinicians, with standards and routines developed long after initiation. Clinicians should endeavor towards a basic understanding even of emerging technologies so that they can direct its use. The intent of this review is to describe the current state of rapidly evolving generative artificial intelligence (GAI), and to explore both how pediatric gastroenterology practice may benefit as well as challenges that will be faced., Recent Findings: Although little research demonstrating the acceptance, practice, and outcomes associated with GAI in pediatric gastroenterology is published, there are relevant data adjacent to the specialty and overwhelming potential as professed in the media. Best practice guidelines are widely developed in academic publishing and resources to initiate and improve practical user skills are prevalent. Initial published evidence supports broad acceptance of the technology as part of medical practice by clinicians and patients, describes methods with which higher quality GAI can be developed, and identifies the potential for bias and disparities resulting from its use. GAI is broadly available as a digital tool for incorporation into medical practice and holds promise for improved quality and efficiency of care, but investigation into how GAI can best be used remains at an early stage despite rapid evolution of the technology., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Women that present to the clinic with established breast cancer metastases have limited treatment options. Yet, the majority of preclinical studies are actually not directed at developing treatment regimens for established metastatic disease. In this review we will discuss the current state of preclinical macro-metastatic breast cancer models, including, but not limited to syngeneic GEMM, PDX and xenografts. Challenges within these models which are often overlooked include fluorophore-immunogenic neoantigens, differences in experimental vs spontaneous metastasis and tumor heterogeneity. Furthermore, due to cell plasticity in the tumor immune microenvironment (TIME) of the metastatic landscape, the treatment efficacy of newly approved immune checkpoint blockade (ICB) may differ in metastatic sites as compared to primary localized tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Cyclic vomiting syndrome (CVS) is a disorder of gut-brain interaction which has a wide clinical spectrum. Clinical action plans have been developed to address and to facilitate treatment in the setting of complex, chronic medical conditions. The CVS Action Plan was developed to meet the chronic and acute care needs of children and adults with CVS. While this tool has not been tested for clinical efficacy as was shown with action plans for functional constipation, anecdotal and indirect evidence supports its use. The CVS Action Plan has the potential to enhance outcomes by simplifying home management and streamlining disease recognition and acute care in the emergency department., (© 2024 John Wiley & Sons Ltd.)

Breast cancer kills hundreds of thousands of people every year. Rapid progress over the past two decades has increased our understanding of the genetic and environmental risk factors for disease. It has also shed light on drivers of tumor progression and the molecular landscape underpinning tumor heterogeneity, as well as the role of the microenvironment and the immune system. These strides forward should lead to more effective and tailored therapies for early- and late-stage patients., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)

Introduction: Treatment for melanoma after a positive sentinel lymph node biopsy includes nodal observation or lymphadenectomy. Important considerations for management, however, involve balancing the risk of recurrence and the risk of lymphedema after lymphadenectomy., Methods: From the Merative MarketScan Research Databases, adult patients were queried from 2007 to 2021. International Classification of Disease, Ninth (ICD-9) and Tenth (ICD-10) Editions, diagnosis codes and Current Procedural Terminology codes were used to identify patients with melanoma diagnoses who underwent an index melanoma excision with a positive sentinel lymph node biopsy (SLNB). Main outcomes were completion lymph node dissection (CLND) utilization after a positive SLNB, developing lymphedema with or without CLND, and nodal basin recurrence 3 months or more after index excision. Subanalyses stratified by index excision year (2007-2017 and 2018-2021) and propensity score matched were additionally conducted. Demographics and comorbidities (measured by Elixhauser index) were recorded., Results: A total of 153,085,453 patients were identified. Of those, 359,298 had a diagnosis of melanoma, and 202,456 patients underwent an excision procedure. The study cohort comprised 3717 patients with a melanoma diagnosis who underwent an excision procedure and had a positive SLNB. The mean age of the study cohort was 49 years, 57% were male, 41% were geographically located in the South, and 24% had an Elixhauser index of 4+. Among the 350 patients who did not undergo CLND, 10% experienced recurrence and 22% developed lymphedema. A total of 3367 patients underwent CLND, of which 8% experienced recurrence and 20% developed lymphedema. Completion lymph node dissection did not significantly affect risk of recurrence [odds ratio (OR), 1.370, P = 0.090] or lymphedema (OR, 1.114, P = 0.438). After stratification and propensity score matching, odds of experiencing lymphedema (OR, 1.604, P = 0.058) and recurrence (OR, 1.825, P = 0.058) after CLND were not significantly affected. Rates of CLND had significantly decreased (P < 0.001) overtime, without change in recurrence rate (P = 0.063)., Conclusions: Electing for nodal observation does not increase the risk of recurrence or reduce risk of lymphedema. Just as CLND does not confer survival benefit, its decreased utilization has not increased recurrence rate., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A with zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages toward an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 and Fgfr1, and induces an interferon (IFN) response uniformly across models. The induction of an IFN response is partially due to the inhibition of Sox4 translation by zotatifin. A similar induction of IFN-stimulated genes was observed in breast cancer patient biopsies following zotatifin treatment. Surprisingly, zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened IFN response, resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for zotatifin, and provide a rationale for new combination regimens consisting of zotatifin and chemotherapy or immunotherapy as treatments for TNBC.

Long noncoding RNAs (lncRNA) play an important role in gene regulation in both normal tissues and cancer. Targeting lncRNAs is a promising therapeutic approach that has become feasible through the development of gapmer antisense oligonucleotides (ASO). Metastasis-associated lung adenocarcinoma transcript (Malat1) is an abundant lncRNA whose expression is upregulated in several cancers. Although Malat1 increases the migratory and invasive properties of tumor cells, its role in the tumor microenvironment (TME) is still not well defined. We explored the connection between Malat1 and the tumor immune microenvironment (TIME) using several immune-competent preclinical syngeneic Tp53-null triple-negative breast cancer (TNBC) mouse models that mimic the heterogeneity and immunosuppressive TME found in human breast cancer. Using a Malat1 ASO, we were able to knockdown Malat1 RNA expression resulting in a delay in primary tumor growth, decreased proliferation, and increased apoptosis. In addition, immunophenotyping of tumor-infiltrating lymphocytes revealed that Malat1 inhibition altered the TIME, with a decrease in immunosuppressive tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) as well as an increase in cytotoxic CD8+ T cells. Malat1 depletion in tumor cells, TAMs, and MDSCs decreased immunosuppressive cytokine/chemokine secretion whereas Malat1 inhibition in T cells increased inflammatory secretions and T-cell proliferation. Combination of a Malat1 ASO with chemotherapy or immune checkpoint blockade (ICB) improved the treatment responses in a preclinical model. These studies highlight the immunostimulatory effects of Malat1 inhibition in TNBC, the benefit of a Malat1 ASO therapeutic, and its potential use in combination with chemotherapies and immunotherapies., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Patients with spinal abnormalities often struggle with fecal and/or urinary incontinence (up to 87 and 92%, respectively) and require a collaborative approach to bowel management in conjunction., Methods: To define existing approaches and propose state-of-the-art bowel management, a literature search was performed using Medline/PubMed, Google Scholar, Cochrane, and EMBASE databases and focusing on the manuscripts published July 2013 and July 2023., Results: Patients with spinal anomalies have impaired innervation of the rectum and anal canal, decreasing the success rate from laxatives and rectal enemas. Thus, transanal irrigations and antegrade flushes are widely utilized in this group of patients. Based on spinal MRI, the potential for bowel control in these children depends on age, type, and lesion level. On referral for bowel management, a contrast study is performed to assess colonic motility and evacuation of stool, followed by a series of abdominal X-rays to define colonic emptying and adjust the regimen. The options for management include laxatives, rectal enemas, transanal irrigations, antegrade flushes, and the creation of a stoma. Approximately 22-71% of patients achieve social continence dependent on the type and level of the lesion., Conclusion: Patients with spinal anomalies require a thorough assessment for continence potential and stool burden prior to initiation of bowel management. The optimal treatment option is defined according to the patient's age, anatomy, and mobility. The likelihood of independent bowel regimen administration should be discussed with the patients and their caregivers.

Objectives: The purpose of our study is to compare in-person and telehealth pediatric care ambulatory visits for gastroenterology (GI) at the Nemours Children's Health System in the Delaware Valley (NCH-DV) based on geospatial, demographic, socioeconomic, and digital disparities., Methods: Characteristics of 26,565 patient encounters from January 2019 to December 2020 were analyzed. U.S. Census Bureau geographic identifiers were assigned to each participant and aligned with the American Community Survey (2015-2019) socioeconomic and digital outcomes. Reported odds ratios (OR) are telehealth encounter/in-person encounter., Results: GI telehealth usage increased 145-fold in 2020 compared to 2019 for NCH-DV. Comparing telehealth to in-person usage in 2020 revealed that GI patients who required a language translator were 2.2-fold less likely to choose telehealth [individual level adjusted OR (I-OR a ) [95% confidence interval, CI], 0.45 [0.30-0.66], P < 0.001]. Individuals of Hispanic ethnicity or non-Hispanic Black or African American race are 1.3-1.4-fold less likely to utilize telehealth than non-Hispanic Whites (I-OR a [95% CI], 0.73 [0.59-0.89], P = 0.002 and 0.76 [0.60-0.95], P = 0.02, respectively). Households in census block groups (BG) that are more likely to utilize telehealth: have broadband access (BG-OR = 2.51 [1.22-5.31], P = 0.014); are above the poverty level (BG-OR = 4.44 [2.00-10.24], P < 0.001); own their own home (BG-OR = 1.79 [1.25-2.60], P = 0.002); and have a bachelor's degree or higher (BG-OR = 6.55 [3.25-13.80], P < 0.001)., Conclusions: Our study is the largest reported pediatric GI telehealth experience in North America that describes racial, ethnic, socioeconomic, and digital inequities. Advocacy and research for pediatric GI focused on telehealth equity and inclusion is urgently needed., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

After an initial pull-though, patients with Hirschsprung disease (HD) can present with obstructive symptoms, Hirschsprung-associated enterocolitis (HAEC), failure to thrive, or fecal soiling. This current review focuses on algorithms for evaluation and treatment in children with HD as a part of a manuscript series on updates in bowel management. In constipated patients, anatomic causes of obstruction should be excluded. Once anatomy is confirmed to be normal, laxatives, fiber, osmotic laxatives, or mechanical management can be utilized. Botulinum toxin injections are performed in all patients with HD before age five because of the nonrelaxing sphincters that they learn to overcome with increased age. Children with a patulous anus due to iatrogenic damage of the anal sphincters are offered sphincter reconstruction. Hypermotility is managed with antidiarrheals and small-volume enemas. Family education is crucial for the early detection of HAEC and for performing at-home rectal irrigations.

Background: Functional constipation (FC) affects up to 32% of the pediatric population, and some of these patients are referred to pediatric surgery units to manage their constipation and/or fecal incontinence. The aim of the current paper is to report the recent updates on the evaluation and management of children with FC as a part of a manuscript series on bowel management in patients with anorectal malformations, Hirschsprung disease, spinal anomalies, and FC., Methods: A literature search was performed using Medline/PubMed, Google Scholar, Cochrane, and EMBASE databases and focusing on the manuscripts published within the last 5-10 years., Results: The first step of management of children with FC is to exclude Hirschsprung disease with a contrast study, examination under anesthesia, anorectal manometry (AMAN). If AMAN shows absent rectoanal inhibitory reflex, a rectal biopsy is performed. Internal sphincter achalasia or high resting pressures indicate botulinum toxin injection. Medical management options include laxatives, rectal enemas, transanal irrigations, and antegrade flushes. Those who fail conservative treatment require further assessment of colonic motility and can be candidates for colonic resection. The type of resection (subtotal colonic resection vs. Deloyer's procedure) can be guided with a balloon expulsion test., Conclusion: Most of the patients with FC referred for surgical evaluation can be managed conservatively. Further studies are required to determine an optimal strategy of surgical resection in children unresponsive to medical treatment.

Telehealth (TH) broadly encompasses remote activities of clinical care (telemedicine), provider and patient education, and general health services. The use of synchronous video for TH first occurred in 1964 and then catapulted to the forefront in 2020 during the coronavirus disease 2019 public health emergency. Due to the sudden need for increased TH utilization by nearly all health care providers at that time, TH became essential to clinical practice. However, its sustainable future is unclear in part given that best practices for TH in pediatric gastroenterology (GI), hepatology, and nutrition remain undefined and non-standardized. Key areas for review include historical perspective, general and subspeciality usage, health care disparities, quality of care and the provider-patient interaction, logistics and operations, licensure and liability, reimbursement and insurance coverage, research and quality improvement (QI) priorities, and future use of TH in pediatric GI with a call for advocacy. This position paper from the Telehealth Special Interest Group of North American Society of Gastroenterology, Hepatology and Nutrition provides recommendations for pediatric GI-focused TH best practices, reviews areas for research and QI growth, and presents advocacy opportunities., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

A better understanding of the mechanisms regulating cancer metastasis is critical to develop new therapies and decrease mortality. Emerging evidence suggests that the interactions between tumor cells and the host immune system play important roles in establishing metastasis. Tumor cells are able to recruit immune cells, which in turn promotes tumor cell invasion, intravasation, survival in circulation, extravasation, and colonization in different organs. The tumor-host immunological interactions also generate a premetastatic niche in distant organs which facilitates metastasis. In this review, we summarize the recent findings on how tumor cells and immune cells regulate each other to coevolve and promote the formation of metastases at the major organ sites of metastasis.

Metastatic cancer is almost always terminal, and more than 90% of cancer deaths result from metastatic disease. Combating cancer metastasis and post-therapeutic recurrence successfully requires understanding each step of metastatic progression. This review describes the current state of knowledge of the etiology and mechanism of cancer progression from primary tumor growth to the formation of new tumors in other parts of the body. Open questions, avenues for future research, and therapeutic approaches with the potential to prevent or inhibit metastasis through personalization to each patient's mutation and/or immune profile are also highlighted., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Functional restoration following major peripheral nerve injury (PNI) is challenging, given slow axon growth rates and eventual regenerative pathway degradation in the absence of axons. We are developing tissue-engineered nerve grafts (TENGs) to simultaneously "bridge" missing nerve segments and "babysit" regenerative capacity by providing living axons to guide host axons and maintain the distal pathway. TENGs were biofabricated using porcine neurons and "stretch-grown" axon tracts. TENG neurons survived and elicited axon-facilitated axon regeneration to accelerate regrowth across both short (1 cm) and long (5 cm) segmental nerve defects in pigs. TENG axons also closely interacted with host Schwann cells to maintain proregenerative capacity. TENGs drove regeneration across 5-cm defects in both motor and mixed motor-sensory nerves, resulting in dense axon regeneration and electrophysiological recovery at levels similar to autograft repairs. This approach of accelerating axon regeneration while maintaining the pathway for long-distance regeneration may achieve recovery after currently unrepairable PNIs.

Signal transducer and activator of transcription 5 (STAT5) promotes cell survival and instigates breast tumor formation, and in the normal breast it also drives alveolar differentiation and lactogenesis. However, whether STAT5 drives a differentiated phenotype in breast tumorigenesis and therefore impacts cancer spread and metastasis is unclear. We found in two genetically engineered mouse models of breast cancer that constitutively activated Stat5a (Stat5a ca ) caused precancerous mammary epithelial cells to become lactogenic and evolve into tumors with diminished potential to metastasize. We also showed that STAT5a ca reduced the migratory and invasive ability of human breast cancer cell lines in vitro. Furthermore, we demonstrated that STAT5a ca overexpression in human breast cancer cells lowered their metastatic burden in xenografted mice. Moreover, RPPA, Western blotting, and studies of ChIPseq data identified several EMT drivers regulated by STAT5. In addition, bioinformatic studies detected a correlation between STAT5 activity and better prognosis of breast cancer patients. Together, we conclude that STAT5 activation during mammary tumorigenesis specifies a tumor phenotype of lactogenic differentiation, suppresses EMT, and diminishes potential for subsequent metastasis., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Malone antegrade continence enemas (MACE) provide a conduit in which the patient can achieve improved continence, be clean of stool, and gain independence in maintaining bowel function. The Mini-ACE® is a low-profile balloon button that is used to facilitate the administration of antegrade enemas. We sought to describe our practice and short-term outcomes., Methods: This work is a retrospective review of the Mini-ACE® appendicostomy button from April 2019 to March 2021, with follow-up concluding in October 2021. Patient demographics, colorectal diagnoses, and outcomes were examined., Results: Forty-three patients underwent Mini-ACE® placement; 22 (51%) were male. The average age at Mini-ACE® insertion was 9.2 years (range 3-20 years). The most common diagnoses were functional constipation in 19 (44%), anorectal malformation in 15 (35%), and Hirschsprung disease in 3 (7%), spinal differences 3 (7%). There were no intra-operative complications, but 5 (12%) required prolapse resection. The median length of stay was two days (IQR 1, 4). Patients achieved self-catheterization at 4.5 [3,7] months from MACE creation, with 38 children (88%) reporting excellent success in remaining clean of stool., Conclusion: The Mini-ACE® appears to be a safe and low-profile option for antegrade continence enema access. Further research is needed directly comparing complications and patient satisfaction rates between different MACE devices and overall quality of life., Level of Evidence: Level IV., (Copyright © 2021. Published by Elsevier Inc.)

Cell-extracellular matrix (ECM) interactions represent fundamental exchanges during tumor progression, yet how particular signal-transduction factors prompt the conversion of tumor cells into migratory populations capable of systemic spread during metastasis remains elusive. We demonstrate that the noncanonical Wnt receptor, Ror2, regulates tumor cell-driven matrix remodeling and invasion in breast cancer. Ror2 loss-of-function (LOF) triggers the disruption of E-cadherin within tumor cells, accompanied by an increase in tumor cell invasion and collagen realignment in three-dimensional cultures. RNA sequencing of Ror2-deficient organoids further uncovered alterations in actin cytoskeleton, cell adhesion, and collagen cross-linking gene expression programs. Spatially, we pinpoint the up-regulation and redistribution of α 5 and β 3 integrins together with the production of fibronectin in areas of invasion downstream of Ror2 loss. Wnt/β-catenin-dependent and Wnt/Ror2 alternative Wnt signaling appear to regulate distinct functions for tumor cells regarding their ability to modify cell-ECM exchanges during invasion. Furthermore, blocking either integrin or focal adhesion kinase (FAK), a downstream mediator of integrin-mediated signal transduction, abrogates the enhanced migration observed upon Ror2 loss. These results reveal a critical function for the alternative Wnt receptor, Ror2, as a determinant of tumor cell-driven ECM exchanges during cancer invasion and metastasis.

Purpose: Pediatric colorectal problems often require complex multidisciplinary care (MDC), which has been affected by the SARS-CoV-2-2019 (COVID-19) pandemic. We describe our utilization and implementation of telehealth (TH) for pediatric colorectal surgery MDC visits and collate patient satisfaction using TH compared to in-person (IP) visits., Methods: Implementation of a single-institution MDC TH platform to perform patient visits on February 1, 2020 was studied. Following 6 months of implementation, TH visits' characteristics were compared with IP visits in the 3 months before implementation by patient volume, length of clinic visits, and patient satisfaction survey results., Results: Before implementation, 152 (100%) of clinic visits were IP. During the implementation, 87 (37.7%) were TH visits. Seventy-four (49%) were MDC visits, 17 (23%) of these using the TH platform. Each TH visit's median length was 25 minutes (IQR 15-30), while the median length of IP visits was 45 minutes (IQR 30-45). Pre-implementation satisfaction scores were 88.6% positive, while satisfaction scores after implementation were 96.8% positive. None of the patients who utilized the TH platform had an unplanned hospital admission within 24 hours of being seen., Conclusion: Our experience demonstrates that the TH platform can provide an efficient avenue for established patients and families to receive highly complex multidisciplinary follow-up care. High levels of patient satisfaction indicated that TH should become part of the routine care plan for patients who require long-term or consistent follow-up.

Background: The U.S. Food and Drug Administration recommends women with silicone breast implants undergo magnetic resonance imaging surveillance to detect asymptomatic rupture. Screening is costly and often not covered by insurance. The authors assessed awareness of and adherence to these recommendations among patients with silicone breast implants., Methods: The authors searched electronic medical records for patients aged 18 years or older with silicone breast implants placed between 2011 and 2016. Consenting patients were surveyed by telephone using a standardized script to assess awareness of U.S. Food and Drug Administration recommendations, whether they had undergone magnetic resonance imaging screening, and barriers to testing. Patients who declined to participate or could not be contacted were excluded. Demographics and operative data were collected. Odds ratios were calculated with one-sample 95 percent confidence intervals, and Fisher exact tests of independence were conducted under assumptions of normality. Multivariable logistic regression analysis was performed to test for confounding., Results: Of 370 patients meeting inclusion criteria, 109 consented to participate. Adherence to U.S. Food and Drug Administration recommendations was 5.9 percent (95 percent CI, 0.15 to 28.7 percent). There was no difference in adherence between patients undergoing cosmetic versus reconstructive surgery ( p = 1.00; OR, 0.80; 95 percent CI, 1.17 to 2.93), having health insurance ( p = 0.58), or residing in a county with median annual household income greater than that of the state of residence ( p = 0.33)., Conclusions: A small proportion of respondents had undergone magnetic resonance imaging in accordance with U.S. Food and Drug Administration recommendations. Low adherence highlights a potential limitation of current federal surveillance recommendations. Additional research is needed to better characterize adherence to magnetic resonance imaging surveillance recommendations, identify barriers to implementation, and determine whether this recommendation remains valid., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Breast cancer ecosystems are composed of complex cell types, including tumor, stromal and immune cells, each of which can assume diverse phenotypes. Both the heterogeneous composition and spatially distinct tumor microenvironment impact breast cancer progression, treatment response and therapeutic resistance. Thus, a deeper understanding of breast cancer heterogeneity may help facilitate the development of novel therapies and improve outcomes for patients. The advent of paradigm shifting single-cell analysis and spatial pathologies allows for a comprehensive analysis of the tumor ecosystem as well as the interactions between its components at unprecedented resolution. In this review, we discuss the insights gained through single-cell analysis and spatial pathologies on breast cancer heterogeneity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Immunosuppressive elements within the tumor microenvironment, such as tumor-associated macrophages (TAM), can present a barrier to successful antitumor responses by cytolytic T cells. Here we employed preclinical syngeneic p53 null mouse models of triple-negative breast cancer (TNBC) to develop a treatment regimen that harnessed the immunostimulatory effects of low-dose cyclophosphamide coupled with the pharmacologic inhibition of TAMs using either a small-molecule CSF1R inhibitor or an anti-CSF1R antibody. This therapeutic combination was effective in treating several highly aggressive TNBC murine mammary tumor and lung metastasis models. Single-cell RNA sequencing characterized tumor-infiltrating lymphocytes including Th cells and antigen-presenting B cells that were highly enriched in responders to combination therapy. In one model that exhibited long-term posttreatment tumor regression, high-dimensional imaging techniques identified the close spatial localization of B220+/CD86+-activated B cells and CD4+ T cells in tertiary lymphoid structures that were present up to 6 weeks posttreatment. The transcriptional and metabolic heterogeneity of TAMs was also characterized in two closely related claudin-low/mesenchymal subtype tumor models with differential treatment responses. A murine TAM signature derived from the T12 model was highly conserved in human claudin-low breast cancers, and high expression of the TAM signature correlated with reduced overall survival in patients with breast cancer. This TAM signature may help identify human patients with claudin-low breast cancer that will benefit from the combination of cyclophosphamide and anti-CSF1R therapy. These studies illustrate the complexity of the tumor immune microenvironment and highlight different immune responses that result from rational immunotherapy combinations., Significance: Immunostimulatory chemotherapy combined with pharmacologic inhibition of TAMs results in durable treatment responses elicited by Th cells and B cells in claudin-low TNBC models., (©2022 American Association for Cancer Research.)

With the coronavirus disease 2019 public health emergency (PHE), telehealth (TH) became essential for continued delivery of care. Members of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) formed the Telehealth for Pediatric Gastrointestinal Care Now (TPGCN) working group and rapidly organized a telemedicine webinar to provide education and guidance. We aim to describe the webinar development and prospectively assess the effectiveness of this webinar-based educational intervention., Methods: NASPGHAN members who registered for the TPGCN webinar received pre- and post-webinar surveys. Outcome measures included a modified Telehealth Acceptance Model (TAM) survey and a Student Evaluation of Educational Quality (SEEQ) standardized instrument., Results: Seven hundred seventy-six NASPGHAN members participated in the webinar, 147 (33%) completed the pre-webinar survey; of these, 25 of 147 (17%) completed a post-webinar survey. Before the PHE, 50.3% of the pre-webinar survey participants had no TH knowledge. Webinar participants trended to have increased acceptance of TH for follow-up visits (pre-webinar, 68% versus post-webinar, 81%; P = 0.15) and chronic disease care (pre-webinar, 57% vs post-webinar, 81%; P = 0.01). The overall acceptance of TH as shown by TAM pre-webinar was 1.74 ± 0.8, which improved to 1.62 ± 0.8 post-webinar (lower scores indicate greater acceptance; P < 0.001). SEEQ results indicate that webinar material was understandable (post-webinar, 95%). Participants found breakout sessions informative and enjoyable (post-webinar, 91%)., Conclusion: The TPGCN TH webinar was an effective educational intervention that fostered increased TH usage for follow-up and chronic care visits, improved TAM scores, and was well received by participants as seen by high SEEQ scores. Sustained and expanded pediatric gastrointestinal TH usage beyond the coronavirus disease 2019 PHE is expected., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Importance: Although it is widely believed that concealment or deception is required to elicit a placebo response, recent studies with adults suggest that open-label placebo (OLP) (ie, honestly prescribed placebos) can yield significant benefits. No studies of OLP have been performed with children., Objective: To evaluate the efficacy of OLP for the treatment of children and adolescents with functional abdominal pain or irritable bowel syndrome., Design, Setting, and Participants: This multicenter crossover randomized clinical trial was conducted from July 1, 2015, to June 15, 2018, at 3 US centers among children and adolescents aged 8 to 18 years with functional abdominal pain or irritable bowel syndrome defined per Rome III criteria. Statistical analysis was performed from March 1, 2019, to September 30, 2020, on an intention-to-treat basis., Interventions: Patients completed 1 week of observation prior to randomization to 1 of 2 counterbalanced groups: OLP for 3 weeks followed by a 3-week control period or control period for 3 weeks followed by OLP for 3 weeks. During the OLP period, participants took 1.5 mL of an inert liquid placebo twice a day. A standardized method for explaining the OLP was used, and the interaction with clinicians had the same duration and style for both time periods. Hyoscyamine was allowed as a rescue medication., Main Outcomes and Measures: The primary outcome was the mean daily pain score during each of the interventions, measured on a 0- to 100-mm visual analog scale, where higher scores indicated greater pain. The number of rescue medications taken during each intervention served as an objective secondary measure., Results: Thirty patients (mean [SD] age, 14.1 [3.4] years; 24 female participants [80.0%]; 16 [53.3%] with functional abdominal pain and 14 [46.7%] with irritable bowel syndrome) completed the study. The mean (SD) pain scores were significantly lower during OLP treatment compared with the control period (39.9 [18.9] vs 45.0 [14.7]; difference, 5.2; 95% CI, 0.2-10.1; P = .03). Patients took nearly twice as many hyoscyamine pills during the control period compared with during the OLP period (mean [SD] number, 3.8 [5.1] pills vs 2.0 [3.0] pills; difference, 1.8 pills; 95% CI, 0.5-3.1 pills)., Conclusions and Relevance: During OLP, patients with functional abdominal pain or irritable bowel syndrome reported significantly less pain and took significantly fewer pain medications. Open-label placebo may be an effective treatment for children and adolescents with functional abdominal pain or irritable bowel syndrome., Trial Registration: ClinicalTrials.gov Identifier: NCT02389998.

Nerve injury requiring surgical repair often results in poor functional recovery due to the inability of host axons to re-grow long distances and reform meaningful connections with the target muscle. While surgeons can re-route local axon fascicles to the target muscle, there are no technologies to provide an exogenous source of axons without sacrificing healthy nerves. Accordingly, we have developed tissue engineered neuromuscular interfaces (TE-NMIs) as the first injectable microtissue containing motor and sensory neurons in an anatomically-inspired architecture. TE-NMIs provide axon tracts that are intended to integrate with denervated distal structures and preserve regenerative capacity during prolonged periods without host innervation. Following implant, we found that TE-NMI axons promoted Schwann cell maintenance, integrated with distal muscle, and preserved an evoked muscle response out to 20-weeks post nerve transection in absence of innervation from host axons. By repopulating the distal sheath with exogenous axons, TE-NMIs also enabled putative delayed fusion with proximal host axons, a phenomenon previously not achievable in delayed repair scenarios due to distal axon degeneration. Here, we found immediate electrophysiological recovery after fusion with proximal host axons and improved axon maturation and muscle reinnervation at 24-weeks post-transection (4-weeks following delayed nerve fusion). These findings show that TE-NMIs provide the potential to improve functional recovery following delayed nerve repair., Competing Interests: D.K.C is a co-founder of Axonova Medical, LLC, and Innervace, Inc. which are University of Pennsylvania spin-out companies focused on translation of advanced regenerative therapies to treat nervous system disorders. Multiple patents relate to the composition, methods, and use of tissue engineered nervous tissue [U.S. Patent 9,895,399 (D.K.C.), U.S. Patent 10,525,085 (D.K.C.), U.S. Patent Application 16/753,634 (D.K.C), and U.S. Provisional Patent Application 62/937,489 (D.K.C. and J.C.B.)], microtissue-engineered neural networks [U.S. Patent Application 15/032,677 (D.K.C.), U.S. Patent Application 16/093,036 (D.K.C.), and U.S. Provisional Patent Application 63/209,639 (D.K.C., J.C.B., J.M.R.)], and innervated engineered tissue for organ modulation [U.S. Provisional Patent Application 62/758,203 (D.K.C. and S.D.)]. No other author has declared a potential conflict of interest., (© 2022 The Authors.)

Tumor dormancy is a stage in which residual cancer cells remain inactive, but regrowth of dormant cancer cells contributes to recurrence. The complex ecosystem in cancer that promotes cell survival and the factors that eventually overcome growth constraints and result in proliferation remain to be fully elucidated. Doing so may provide new insights and help identify novel strategies to prolong cancer dormancy and prevent disease recurrence. To dissect the molecular pathways and the microenvironments involved in regulation of dormancy, we utilized a novel immunocompetent transgenic model to study minimal residual disease and relapse. This model revealed a significant reorganization of cancer cell structures, stroma, and immune cells, with cancer cells showing dormant cell signatures. Single-cell RNA sequencing uncovered remodeling of myeloid and lymphoid compartments. In addition, the Jagged-1/Notch signaling pathway was shown to regulate many aspects of tumorigenesis, including stem cell development, epithelial-to-mesenchymal transition, and immune cell homeostasis during minimal residual disease. Treatment with an anti-Jagged-1 antibody inhibited the Jagged-1/Notch signaling pathway in tumor cells and the microenvironment, delaying tumor recurrence. These findings uncover a cascade of regulatory changes in the microenvironment during dormancy and identify a therapeutic strategy to undercut these changes., Significance: Single-cell RNA-sequencing analysis reveals dormancy-associated changes in immune and stromal cells and demonstrates a rationale to pursue Jagged-1/Notch pathway inhibition as a viable therapeutic strategy to reduce disease recurrence., (©2021 American Association for Cancer Research.)

Polo-like kinase (PLK) family members play important roles in cell cycle regulation. The founding member PLK1 is oncogenic and preclinically validated as a cancer therapeutic target. Paradoxically, frequent loss of chromosome 5q11-35 which includes PLK2 is observed in basal-like breast cancer. In this study, we found that PLK2 was tumor suppressive in breast cancer, preferentially in basal-like and triple-negative breast cancer (TNBC) subtypes. Knockdown of PLK1 rescued phenotypes induced by PLK2-loss both in vitro and in vivo . We also demonstrated that PLK2 directly interacted with PLK1 at prometaphase through the kinase but not the polo-box domains of PLK2, suggesting PLK2 functioned at least partially through the interaction with PLK1. Furthermore, an improved treatment response was seen in both Plk2-deleted/low mouse preclinical and PDX TNBC models using the PLK1 inhibitor volasertib alone or in combination with carboplatin. Re-expression of PLK2 in an inducible PLK2-null mouse model reduced the therapeutic efficacy of volasertib. In summary, this study delineates the effects of chromosome 5q loss in TNBC that includes PLK2, the relationship between PLK2 and PLK1, and how this may render PLK2-deleted/low tumors more sensitive to PLK1 inhibition in combination with chemotherapy., Competing Interests: Conflict of Interest: CMP is an equity stockholder and board member of BioClassifier and GeneCentric Therapeutics. CMP is also listed as an inventor on patent applications for the Breast PAM50. MTL is a Founder and Limited Partner of StemMed Ltd, and a Manager of StemMed Holdings, LLC, its General Partner. MTL is also a Founder of, and equity holder in, Tvardi Therapeutics Inc. The other authors declare that they have no competing interests.

During the COVID-19 pandemic, medical providers have expanded telehealth into daily practice, with many medical and behavioral health care visits provided remotely over video or through phone. The telehealth market was already facilitating home health care with increasing levels of sophistication before COVID-19. Among the emerging telehealth practices, telephysical therapy; teleneurology; telemental health; chronic care management of congestive heart failure, chronic obstructive pulmonary disease, diabetes; home hospice; home mechanical ventilation; and home dialysis are some of the most prominent. Home telehealth helps streamline hospital/clinic operations and ensure the safety of health care workers and patients. The authors recommend that we expand home telehealth to a comprehensive delivery of medical care across a distributed network of hospitals and homes, linking patients to health care workers through the Internet of Medical Things using in-home equipment, including smart medical monitoring devices to create a "medical smart home." This expanded telehealth capability will help doctors care for patients flexibly, remotely, and safely as a part of standard operations and during emergencies such as a pandemic. This model of "telehomecare" is already being implemented, as shown herein with examples. The authors envision a future in which providers and hospitals transition medical care delivery to the home just as, during the COVID-19 pandemic, students adapted to distance learning and adults transitioned to remote work from home. Many of our homes in the future may have a "smart medical suite" as well as a "smart home office."

Treatment with immune checkpoint blockade (ICB) has resulted in durable responses for a subset of patients with cancer, with predictive biomarkers for ICB response originally identified largely in the context of hypermutated cancers. Although recent clinical data have demonstrated clinical responses to ICB in certain patients with nonhypermutated cancers, previously established ICB response biomarkers have failed to accurately identify which of these patients may benefit from ICB. Here, we demonstrated that a replication stress response (RSR) defect gene expression signature, but not other proposed biomarkers, is associated with ICB response in 12 independent cohorts of patients with nonhypermutated cancer across seven tumor types, including those of the breast, prostate, kidney, and brain. Induction or suppression of RSR deficiencies was sufficient to modulate response to ICB in preclinical models of breast and renal cancers. Mechanistically, we found that despite robust activation of checkpoint kinase 1 signaling in RSR-deficient cancer cells, aberrant replication origin firing caused exhaustion of replication protein A, resulting in accumulation of immunostimulatory cytosolic DNA. We further found that deficient RSR coincided with increased intratumoral dendritic cells in both mouse cancer models and human tumors. Together, this work demonstrates that the RSR defect gene signature can accurately identify patients who may benefit from ICB across numerous nonhypermutated tumor types, and pharmacological induction of RSR defects may further expand the benefits of ICB to more patients.

Dysbiosis of gut microbiota is associated with many pathologies, yet host factors modulating microbiota remain unclear. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition of chronic pelvic pain often with comorbid urinary dysfunction and anxiety/depression, and recent studies find fecal dysbiosis in patients with IC/BPS. We identified the locus encoding acyloxyacyl hydrolase, Aoah , as a modulator of pelvic pain severity in a murine IC/BPS model. AOAH-deficient mice spontaneously develop rodent correlates of pelvic pain, increased responses to induced pelvic pain models, voiding dysfunction, and anxious/depressive behaviors. Here, we report that AOAH-deficient mice exhibit dysbiosis of gastrointestinal (GI) microbiota. AOAH-deficient mice exhibit an enlarged cecum, a phenotype long associated with germ-free rodents, and a "leaky gut" phenotype. AOAH-deficient ceca showed altered gene expression consistent with inflammation, Wnt signaling, and urologic disease. 16S sequencing of stool revealed altered microbiota in AOAH-deficient mice, and GC-MS identified altered metabolomes. Cohousing AOAH-deficient mice with wild-type mice resulted in converged microbiota and altered predicted metagenomes. Cohousing also abrogated the pelvic pain phenotype of AOAH-deficient mice, which was corroborated by oral gavage of AOAH-deficient mice with stool slurry of wild-type mice. Converged microbiota also alleviated comorbid anxiety-like behavior in AOAH-deficient mice. Oral gavage of AOAH-deficient mice with anaerobes cultured from IC/BPS stool resulted in exacerbation of pelvic allodynia. Together, these data indicate that AOAH is a host determinant of normal gut microbiota, and dysbiosis associated with AOAH deficiency contributes to pelvic pain. These findings suggest that the gut microbiome is a potential therapeutic target for IC/BPS.

Introduction: Rumination syndrome involves recurrent regurgitation of food and is believed to be underdiagnosed with patients experiencing long delays in diagnosis. It can be associated with significant social consequences, high rates of school absenteeism, and medical complications such as weight loss. The primary aims of the current review are to assess the literature regarding prevalence, pathophysiology, and treatment outcomes with a focus on neurotypical children and adolescents. Results: Population studies in children/adolescents, 5 years of age or older, range from 0 to 5.1%. There are fewer studies in clinical settings, but the prevalence appears to be higher in patients with other gastrointestinal symptoms, particularly chronic vomiting. While physiologic changes that occur during a rumination episode are well-described, the underlying cause is less well-defined. In general, rumination appears to have similarities to other functional gastrointestinal disorders including dysmotility, possibly inflammation, and an interaction with psychologic function. While diaphragmatic breathing is considered the mainstay of treatment, pediatric data demonstrating efficacy is lacking, especially as an isolated treatment. Conclusion: Pediatric rumination syndrome remains greatly understudied, particularly regarding treatment. There is a need to better define prevalence in both the primary care and subspecialty clinical settings, especially in patients presenting with vomiting or apparent gastroesophageal reflux. There is a need to determine whether treatment of co-morbid conditions results in improvement of rumination. Diaphragmatic breathing needs to be studied and compared to other competing responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Martinez, Rathod, Friesen, Rosen, Friesen and Schurman.)

The epithelial-mesenchymal transition (EMT) has been implicated in conferring stem cell properties and therapeutic resistance to cancer cells. Therefore, identification of drugs that can reprogram EMT may provide new therapeutic strategies. Here, we report that cells derived from claudin-low mammary tumors, a mesenchymal subtype of triple-negative breast cancer, exhibit a distinctive organoid structure with extended "spikes" in 3D matrices. Upon a miR-200 induced mesenchymal-epithelial transition (MET), the organoids switch to a smoother round morphology. Based on these observations, we developed a morphological screening method with accompanying analytical pipelines that leverage deep neural networks and nearest neighborhood classification to screen for EMT-reversing drugs. Through screening of a targeted epigenetic drug library, we identified multiple class I HDAC inhibitors and Bromodomain inhibitors that reverse EMT. These data support the use of morphological screening of mesenchymal mammary tumor organoids as a platform to identify drugs that reverse EMT., (© 2021. The Author(s).)