Interhospital Transport of Children With Peripheral Venous Catheters by Private Vehicle: A Mixed Methods Assessment.

BACKGROUND: Many children seeking emergency care at community hospitals require transport to tertiary centers for definitive management. Interhospital transport via ambulance versus patient's own vehicle (POV) are 2 possible modes of transport; however, presence of a peripheral venous catheter (PIV) can determine transport by ambulance. Caregiver satisfaction, patient comfort, and PIV complications related to POV transport have not been described. OBJECTIVE: The aims of the study were to examine caregivers' satisfaction and perceptions of POV transport in children with/without PIVs and to assess PIV-related complications during transport. METHODS: We performed a mixed-methods, prospective cohort study of children who presented with low-acuity conditions to a community hospital and subsequently required transfer to a pediatric tertiary center. Caregivers of patients with/without PIVs were given the choice of transport by POV or ambulance. Surveys completed after transport used dichotomous, 5-point Likert scale, and open-ended responses to assess satisfaction, perceptions, and PIV-related complications. Responses were quantitatively and qualitatively analyzed accordingly. The receiving hospital assessed PIV integrity. RESULTS: Sixty-nine of 78 eligible patients were enrolled; of those, 67 (97%) elected transport by POV and 55 (82%) completed surveys. Most caregivers had positive responses related to satisfaction, comfort, and safety. Results did not differ significantly between those with/without PIVs. The majority (96%) would choose POV transport again. There were no reported PIV complications; all PIVs were functional upon arrival. Qualitative analysis identified themes of comfort, convenience, and efficiency. CONCLUSIONS: In select scenarios, interfacility transport by POV is preferred by families and doing so with a saline-locked PIV does not result in complications.

Television-Related Head Injuries in Children: A Secondary Analysis of a Large Cohort Study of Head-Injured Children in the Pediatric Emergency Care Applied Research Network.

OBJECTIVE: The objective of the study was to describe the epidemiology, cranial computed tomography (CT) findings, and clinical outcomes of children with blunt head trauma after television tip-over injuries. METHODS: We performed a secondary analysis of children younger than 18 years prospectively evaluated for blunt head trauma at 25 emergency departments (EDs) in the Pediatric Emergency Care Applied Research Network from June 2004 to September 2006. Children injured from falling televisions were included. Patients were excluded if injuries occurred more than 24 hours before ED evaluation or if neuroimaging was obtained before evaluation. Data collected included age, race, sex, cranial CT findings, and clinical outcomes. Clinically important traumatic brain injuries (ciTBIs) were defined as death from TBI, neurosurgery, intubation for more than 24 hours for the TBI, or hospital admission of 2 nights or more for the head injury, in association with TBI on CT. RESULTS: A total of 43,904 children were enrolled into the primary study and 218 (0.5%; 95% confidence interval [CI], 0.4% to 0.6%) were struck by falling televisions. The median (interquartile range) age of the 218 patients was 3.1 (1.9-4.9) years. Seventy-five (34%) of the 218 underwent CT scanning. Ten (13.3%; 95% CI, 6.6% to 23.2%) of the 75 patients with an ED CT had traumatic findings on cranial CT scan. Six patients met the criteria for ciTBI. Three of these patients died. All 6 patients with ciTBIs were younger than 5 years. CONCLUSIONS: Television tip-overs may cause ciTBIs in children, including death, and the most severe injuries occur in children 5 years or younger. These injuries may be preventable by simple preventive measures such as anchoring television sets with straps.

ERß-mediated induction of cystatins results in suppression of TGFß signaling and inhibition of triple-negative breast cancer metastasis.

Triple-negative breast cancer (TNBC) accounts for a disproportionately high number of deaths due to a lack of targeted therapies and an increased likelihood of distant recurrence. Estrogen receptor beta (ERß), a well-characterized tumor suppressor, is expressed in 30% of TNBCs, and its expression is associated with improved patient outcomes. We demonstrate that therapeutic activation of ERß elicits potent anticancer effects in TNBC through the induction of a family of secreted proteins known as the cystatins, which function to inhibit canonical TGFß signaling and suppress metastatic phenotypes both in vitro and in vivo. These data reveal the involvement of cystatins in suppressing breast cancer progression and highlight the value of ERß-targeted therapies for the treatment of TNBC patients.

Antitumor activity of Z-endoxifen in aromatase inhibitor-sensitive and aromatase inhibitor-resistant estrogen receptor-positive breast cancer.

BACKGROUND: The tamoxifen metabolite, Z-endoxifen, demonstrated promising antitumor activity in endocrine-resistant estrogen receptor-positive (ER+) breast cancer. We compared the antitumor activity of Z-endoxifen with tamoxifen and letrozole in the letrozole-sensitive MCF7 aromatase expressing model (MCF7AC1), as well as with tamoxifen, fulvestrant, exemestane, and exemestane plus everolimus in a letrozole-resistant MCF7 model (MCF7LR). METHODS: MCF7AC1 tumor-bearing mice were randomized to control (no drug), letrozole (10 µg/day), tamoxifen (500 µg/day), or Z-endoxifen (25 and 75 mg/kg). Treatment in the letrozole arm was continued until resistance developed. MCF7LR tumor-bearing mice were then randomized to Z-endoxifen (50 mg/kg) or tamoxifen for 4 weeks and tumors harvested for microarray and immunohistochemistry analysis. The antitumor activity of Z-endoxifen in the MCF7LR tumors was further compared in a second in vivo study with exemestane, exemestane plus everolimus, and fulvestrant. RESULTS: In the MCF7AC1 tumors, both Z-endoxifen doses were significantly superior to control and tamoxifen in reducing tumor volumes at 4 weeks. Additionally, the 75 mg/kg Z-endoxifen dose was additionally superior to letrozole. Prolonged letrozole exposure resulted in resistance at 25 weeks. In MCF7LR tumor-bearing mice, Z-endoxifen significantly reduced tumor volumes compared to tamoxifen, letrozole, and exemestane, with no significant differences compared to exemestane plus everolimus and fulvestrant. Additionally, compared to tamoxifen, Z-endoxifen markedly inhibited ERα target genes, Ki67 and Akt expression in vivo. CONCLUSION: In endocrine-sensitive and letrozole-resistant breast tumors, Z-endoxifen results in robust antitumor and antiestrogenic activity compared to tamoxifen and aromatase inhibitor monotherapy. These data support the ongoing development of Z-endoxifen.

Correction: Clinical associations with telomere length in chronic spinal cord injury.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Periodontal Disease and Senescent Cells: New Players for an Old Oral Health Problem?

The recent identification of senescent cells in periodontal tissues has the potential to provide new insights into the underlying mechanisms of periodontal disease etiology. DNA damage-driven senescence is perhaps one of the most underappreciated delayed consequences of persistent Gram-negative bacterial infection and inflammation. Although the host immune response rapidly protects against bacterial invasion, oxidative stress generated during inflammation can indirectly deteriorate periodontal tissues through the damage to vital cell macromolecules, including DNA. What happens to those healthy cells that reside in this harmful environment? Emerging evidence indicates that cells that survive irreparable genomic damage undergo cellular senescence, a crucial intermediate mechanism connecting DNA damage and the immune response. In this review, we hypothesize that sustained Gram-negative bacterial challenge, chronic inflammation itself, and the constant renewal of damaged tissues create a permissive environment for the abnormal accumulation of senescent cells. Based on emerging data we propose a model in which the dysfunctional presence of senescent cells may aggravate the initial immune reaction against pathogens. Further understanding of the role of senescent cells in periodontal disease pathogenesis may have clinical implications by providing more sophisticated therapeutic strategies to combat tissue destruction.

Clinical associations with telomere length in chronic spinal cord injury.

STUDY DESIGN: Cross-sectional study OBJECTIVES: To determine clinical factors associated with telomere length in persons with chronic spinal cord injury (SCI). SETTING: Veterans Affairs Medical Center, Boston, MA. METHODS: Two hundred seventy-eight participants with chronic SCI provided blood samples for measurement of C-reactive protein (CRP), interleukin-6 (IL-6), and telomere length, completed respiratory health questionnaires, underwent dual X-ray absorptiometry (DXA) to assess body fat, and completed spirometry. High-throughput real-time PCR assays were used to assess telomere length in leukocyte genomic DNA. Linear regression models were used to assess cross-sectional associations with telomere length. RESULTS: Telomere length was inversely related to age (p < 0.0001). In age-adjusted models, gender, race, injury duration, %-total and %-trunk fat, body mass index (BMI), %-predicted forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), chronic cough or phlegm, CRP, IL-6, wheeze, smoking, diabetes, heart disease, chronic obstructive pulmonary disease (COPD), skin ulcer, urinary tract infection (UTI), or chest illness history were not significantly associated with telomere length. There was a suggestive age-adjusted association between persons with the most severe SCI (cervical motor complete and AIS C) and shorter telomere length (p = 0.055), an effect equivalent to ~8.4 years of premature aging. There were similar age-adjusted associations with telomere length between persons using a wheelchair (p = 0.059) and persons with chronic urinary catheter use (p = 0.082) compared to persons without these characteristics. CONCLUSIONS: Our results suggest that clinical characteristics such as decreased mobility and bladder dysfunction that are common in individuals with more severe SCI are associated with shorter telomere length.

TIEG and estrogen modulate SOST expression in the murine skeleton.

TIEG knockout (KO) mice exhibit a female-specific osteopenic phenotype and altered expression of TIEG in humans is associated with osteoporosis. Gene expression profiling studies identified sclerostin as one of the most highly up-regulated transcripts in the long bones of TIEG KO mice relative to WT littermates suggesting that TIEG may regulate SOST expression. TIEG was shown to substantially suppress SOST promoter activity and the regulatory elements through which TIEG functions were identified using promoter deletion and chromatin immunoprecipitation assays. Knockdown of TIEG in IDG-SW3 osteocyte cells using shRNA and CRISPR-Cas9 technology resulted in increased SOST expression and delayed mineralization, mimicking the results obtained from TIEG KO mouse bones. Given that TIEG is an estrogen regulated gene, and as changes in the hormonal milieu affect SOST expression, we performed ovariectomy (OVX) and estrogen replacement therapy (ERT) studies in WT and TIEG KO mice followed by miRNA and mRNA sequencing of cortical and trabecular compartments of femurs. SOST expression levels were considerably higher in cortical bone compared to trabecular bone. In cortical bone, SOST expression was increased following OVX only in WT mice and was suppressed following ERT in both genotypes. In contrast, SOST expression in trabecular bone was decreased following OVX and significantly increased following ERT. Interestingly, a number of miRNAs that are predicted to target sclerostin exhibited inverse expression levels in response to OVX and ERT. These data implicate important roles for TIEG and estrogen-regulated miRNAs in modulating SOST expression in bone.

Combined Pediatric ED/Inpatient Unit Concept Catches On with Maryland Community Hospitals.

Some community hospitals that struggle to maintain a financially viable pediatric inpatient service have found success with a model that combines their pediatric inpatient unit with a pediatric ED. The approach was developed first at Howard County General Hospital in Columbia, MD, nearly two decades ago, and has been duplicated at other community hospitals in the state. Now, community hospitals elsewhere are taking a look. In addition to the financial benefits, users of this approach say that it can improve throughput while also boosting patient and provider satisfaction. The concept involves placing the pediatric inpatient unit adjacent to the pediatric ED so that pediatric physicians and nurses can float between the two sides of the unit as needed, maximizing resources. Although the approach initially takes volume away from the adult ED, administrators say hospitals generally replace this volume within two years. Pioneers of the combined model note community hospitals must engage in at least 10,000-12,000 pediatric encounters in the ED every year for the combined pediatric inpatient unit/pediatric ED model to be successful.

Mutual enhancement of differentiation of osteoblasts and osteocytes occurs through direct cell-cell contact.

There is increasing evidence that osteocytes regulate multiple aspects of bone remodeling through bi-directional communication with osteoblasts. This is potentially mediated through cell-cell contact via osteocytic dendritic processes, through the activity of secreted factors, or both. To test whether cell-cell contact affects gene expression patterns in osteoblasts and osteocytes, we used a co-culture system where calvarial osteoblasts and IDG-SW3 osteocytes were allowed to touch through a porous membrane, while still being physically separated to allow for phenotypic characterization. Osteoblast/osteocyte cell-contact resulted in up-regulation of osteoblast differentiation genes in the osteoblasts, when compared to wells where no cell contact was allowed. Examination of osteocyte gene expression when in direct contact with osteoblasts also revealed increased expression of osteocyte-specific genes. These data suggest that physical contact mutually enhances both the osteoblastic and osteocytic character of each respective cell type. Interestingly, Gja1 (a gap junction protein) was increased in the osteoblasts only when in direct contact with the osteocytes, suggesting that Gja1 may mediate some of the effects of direct cell contact. To test this hypothesis, we treated the direct contact system with the gap junction inhibitor 18-alpha-glycyrrhetinic acid and found that Bglap expression was significantly inhibited. This suggests that osteocytes may regulate late osteoblast differentiation at least in part through Gja1. Identification of the specific factors involved in the enhancement of differentiation of both osteoblasts and osteocytes when in direct contact will uncover new biology concerning how these bone cells communicate.

Accuracy of the abdominal examination for identifying children with blunt intra-abdominal injuries.

OBJECTIVE: To determine the accuracy of complaints of abdominal pain and findings of abdominal tenderness for identifying children with intra-abdominal injury (IAI) stratified by Glasgow Coma Scale (GCS) score. STUDY DESIGN: This was a prospective, multicenter observational study of children with blunt torso trauma and a GCS score ≥13. We calculated the sensitivity of abdominal findings for IAI with 95% CI stratified by GCS score. We examined the association of isolated abdominal pain or tenderness with IAI and that undergoing acute intervention (therapeutic laparotomy, angiographic embolization, blood transfusion, or ≥2 nights of intravenous fluid therapy). RESULTS: Among the 12 044 patients evaluated, 11 277 (94%) had a GCS score of ≥13 and were included in this analysis. Sensitivity of abdominal pain for IAI was 79% (95% CI, 76%-83%) for patients with a GCS score of 15, 51% (95% CI, 37%-65%) for patients with a GCS score of 14, and 32% (95% CI, 14%-55%) for patients with a GCS score of 13. Sensitivity of abdominal tenderness for IAI also decreased with decreasing GCS score: 79% (95% CI, 75%-82%) for a GCS score of 15, 57% (95% CI, 42%-70%) for a GCS score of 14, and 37% (95% CI, 19%-58%) for a GCS score of 13. Among patients with isolated abdominal pain and/or tenderness, the rate of IAI was 8% (95% CI, 6%-9%) and the rate of IAI undergoing acute intervention was 1% (95% CI, 1%-2%). CONCLUSION: The sensitivity of abdominal findings for IAI decreases as GCS score decreases. Although abdominal computed tomography is not mandatory, the risk of IAI is sufficiently high that diagnostic evaluation is warranted in children with isolated abdominal pain or tenderness.

Isolation and characterization of bone mesenchymal cell small extracellular vesicles using a novel mouse model.

Extracellular vesicles (EVs) are key mediators of cell-cell communication and are involved in transferring specific biomolecular cargo to recipient cells to regulate their physiological functions. A major challenge in the understanding of EV function in vivo is the difficulty ascertaining the origin of the EV particles. The recent development of the "Snorkel-tag", which includes EV-membrane-targeted CD81 fused to a series of extra-vesicular protein tags, can be used to mark EVs originating from a specific source for subsequent isolation and characterization. We developed an in vivo mouse model, termed "CAGS-Snorkel", which expresses the Snorkel-tag under the control of the Cre-lox system, and crossed this mouse with either Prx1-Cre (mesenchymal progenitors) or Ocn-Cre (osteoblasts/osteocytes) and isolated Snorkel-tagged EVs from the mouse bone marrow plasma using a magnetic bead affinity column. miRNA-sequencing was performed on the isolated EVs, and although similar profiles were observed, a few key miRNAs involved in bone metabolism (miR-106b-5p, miRs-19b-3p and miRs-219a-5p) were enriched in the Ocn-derived relative to the Prx1-derived EV subpopulations. To characterize the effects of these small EVs on a bone cell target, cultured mouse bone marrow stromal cells (mBMSCs) were treated with Prx1 or Ocn EVs, and mRNA-sequencing was performed. Pathways involved in ossification, bone development and extracellular matrix interactions were regulated by both EV subpopulations, whereas a few pathways including advanced glycation end-products (AGE) signaling, were uniquely regulated in the Ocn EV subpopulation, underlying important biological effects of specific EV subpopulations within the bone marrow microenvironment. These data demonstrate that EV isolation in vivo using the CAGS-Snorkel mouse model is a useful tool in characterizing the cargo and understanding the biology of tissue-specific EVs. Moreover, while bone mesenchymal cell populations share a common EV secretory profile, we uncover key differences based on the stage of osteoblastic differentiation that may have important biological consequences.

Extracellular vesicles (EVs) are small, lipid-based particles that are produced by all cells in the body, and function as a method of communication among different cells in a particular microenvironment. However, identification of the source of the EVs is difficult following export from the cell which the EV is produced. To facilitate the identification and characterization of the active molecules contained within EVs from a particular cell-type, we developed a new mouse model (CAGS-Snorkel) which allows for identification of the EV source cell using specific protein molecules on the EVs in only one particular cell- or tissue-type. As a proof-of-principle, we compared the microRNA EV cargo in cells from early bone cell progenitors and mature bone cells in the bone marrow microenvironment. We find that a number of microRNAs, molecules involved in the function and regulation of cellular processes, are expressed both in common and specifically within those two cell types. Notably, when purified EV subpopulations from these cell types were used to treat bone cell cultures, we find both common and unique gene expression and molecular pathway profiles. This work describes a new mouse model that will be useful in understanding how EVs function to carry important cellular information.

Senotherapeutic drug treatment ameliorates chemotherapy-induced cachexia.

Cachexia is a debilitating skeletal muscle wasting condition for which we currently lack effective treatments. In the context of cancer, certain chemotherapeutics cause DNA damage and cellular senescence. Senescent cells exhibit chronic activation of the transcription factor NF-κB, a known mediator of the proinflammatory senescence-associated secretory phenotype (SASP) and skeletal muscle atrophy. Thus, targeting NF-κB represents a logical therapeutic strategy to alleviate unintended consequences of genotoxic drugs. Herein, we show that treatment with the IKK/NF-κB inhibitor SR12343 during a course of chemotherapy reduces markers of cellular senescence and the SASP in liver, skeletal muscle, and circulation and, correspondingly, attenuates features of skeletal muscle pathology. Lastly, we demonstrate that SR12343 mitigates chemotherapy-induced reductions in body weight, lean mass, fat mass, and muscle strength. These findings support senescent cells as a promising druggable target to counteract the SASP and skeletal muscle wasting in the context of chemotherapy.

Osteochondroprogenitor cells and neutrophils expressing p21 and senescence markers modulate fracture repair.

Cells expressing features of senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Here, we used skeletal injury as a model and identified the rapid appearance following fracture of p21+ cells expressing senescence markers, mainly as osteochondroprogenitors (OCHs) and neutrophils. Targeted genetic clearance of p21+ cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, p21+ cell clearance did not alter bone loss due to aging; conversely, p16+ cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Following fracture, p21+ neutrophils were enriched in signaling pathways known to induce paracrine stromal senescence, while p21+ OCHs were highly enriched in senescence-associated secretory phenotype factors known to impair bone formation. Further analysis revealed an injury-specific stem cell-like OCH subset that was p21+ and highly inflammatory, with a similar inflammatory mesenchymal population (fibro-adipogenic progenitors) evident following muscle injury. Thus, intercommunicating senescent-like neutrophils and mesenchymal progenitor cells were key regulators of tissue repair in bone and potentially across tissues. Moreover, our findings established contextual roles of p21+ versus p16+ senescent/senescent-like cells that may be leveraged for therapeutic opportunities.

Osteochondroprogenitor cells and neutrophils expressing p21 and senescence markers modulate fracture repair.

Cells expressing features of senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Here, we used skeletal injury as a model and identified the rapid appearance following fracture of p21+ cells expressing senescence markers, mainly as osteochondroprogenitors (OCHs) and neutrophils. Targeted genetic clearance of p21+ cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, p21+ cell clearance did not alter bone loss due to aging; conversely, p16+ cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Following fracture, p21+ neutrophils were enriched in signaling pathways known to induce paracrine stromal senescence, while p21+ OCHs were highly enriched in senescence-associated secretory phenotype factors known to impair bone formation. Further analysis revealed an injury-specific stem cell-like OCH subset that was p21+ and highly inflammatory, with a similar inflammatory mesenchymal population (fibro-adipogenic progenitors) evident following muscle injury. Thus, intercommunicating senescent-like neutrophils and mesenchymal progenitor cells are key regulators of tissue repair in bone and potentially across tissues. Moreover, our findings establish contextual roles of p21+ vs p16+ senescent/senescent-like cells that may be leveraged for therapeutic opportunities.

Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial.

Preclinical evidence demonstrates that senescent cells accumulate with aging and that senolytics delay multiple age-related morbidities, including bone loss. Thus, we conducted a phase 2 randomized controlled trial of intermittent administration of the senolytic combination dasatinib plus quercetin (D + Q) in postmenopausal women (n = 60 participants). The primary endpoint, percentage changes at 20 weeks in the bone resorption marker C-terminal telopeptide of type 1 collagen (CTx), did not differ between groups (median (interquartile range), D + Q -4.1% (-13.2, 2.6), control -7.7% (-20.1, 14.3); P = 0.611). The secondary endpoint, percentage changes in the bone formation marker procollagen type 1 N-terminal propeptide (P1NP), increased significantly (relative to control) in the D + Q group at both 2 weeks (+16%, P = 0.020) and 4 weeks (+16%, P = 0.024), but was not different from control at 20 weeks (-9%, P = 0.149). No serious adverse events were observed. In exploratory analyses, the skeletal response to D + Q was driven principally by women with a high senescent cell burden (highest tertile for T cell p16 (also known as CDKN2A) mRNA levels) in which D + Q concomitantly increased P1NP (+34%, P = 0.035) and reduced CTx (-11%, P = 0.049) at 2 weeks, and increased radius bone mineral density (+2.7%, P = 0.004) at 20 weeks. Thus, intermittent D + Q treatment did not reduce bone resorption in the overall group of postmenopausal women. However, our exploratory analyses indicate that further studies are needed testing the hypothesis that the underlying senescent cell burden may dictate the clinical response to senolytics. ClinicalTrials.gov identifier: NCT04313634 .

Identification of Rorß targets in cultured osteoblasts and in human bone.

Control of osteoblastic bone formation involves the cumulative action of numerous transcription factors, including both activating and repressive functions that are important during specific stages of differentiation. The nuclear receptor retinoic acid receptor-related orphan receptor ß (Rorß) has been recently shown to suppress the osteogenic phenotype in cultured osteoblasts, and is highly upregulated in bone marrow-derived osteogenic precursors isolated from aged osteoporotic mice, suggesting Rorß is an important regulator of osteoblast function. However the specific gene expression patterns elicited by Rorß are unknown. Using microarray analysis, we identified 281 genes regulated by Rorß in an MC3T3-E1 mouse osteoblast cell model (MC3T3-Rorß-GFP). Pathway analysis revealed alterations in genes involved in MAPK signaling, genes involved in extracellular matrix (ECM) regulation, and cytokine-receptor interactions. Whereas the identified Rorß-regulated ECM genes normally decline during osteoblastic differentiation, they were highly upregulated in this non-mineralizing MC3T3-Rorß-GFP model system, suggesting that Rorß may exert its anti-osteogenic effects through ECM disruption. Consistent with these in vitro findings, the expression of both RORß and a subset of RORß-regulated genes were increased in bone biopsies from postmenopausal women (73±7 years old) compared to premenopausal women (30±5 years old), suggesting a role for RORß in human age-related bone loss. Collectively, these data demonstrate that Rorß regulates known osteogenic pathways, and may represent a novel therapeutic target for age-associated bone loss.

The prevalence of traumatic brain injuries after minor blunt head trauma in children with ventricular shunts.

STUDY OBJECTIVE: We compare the prevalence of clinically important traumatic brain injuries and the use of cranial computed tomography (CT) in children with minor blunt head trauma with and without ventricular shunts. METHODS: We performed a secondary analysis of a prospective observational cohort study of children with blunt head trauma presenting to a participating Pediatric Emergency Care Applied Research Network emergency department. For children with Glasgow Coma Scale (GCS) scores greater than or equal to 14, we compared the rates of clinically important traumatic brain injuries (defined as a traumatic brain injury resulting in death, neurosurgical intervention, intubation for more than 24 hours, or hospital admission for at least 2 nights for management of traumatic brain injury in association with positive CT scan) and use of cranial CT for children with and without ventricular shunts. RESULTS: Of the 39,732 children with blunt head trauma and GCS scores greater than or equal to 14, we identified 98 (0.2%) children with ventricular shunts. Children with ventricular shunts had more frequent CT use: (45/98 [46%] with shunts versus 13,858/39,634 [35%] without; difference 11%; 95% confidence interval 1% to 21%) but a similar rate of clinically important traumatic brain injuries (1/98 [1%] with shunts versus 346/39,619 [0.9%] without; difference 0.1%; 95% confidence interval -0.3% to 5%). The one child with a ventricular shunt who had a clinically important traumatic brain injury had a known chronic subdural hematoma that was larger after the head trauma compared with previous CT; the child underwent hematoma evacuation. CONCLUSION: Children with ventricular shunts had higher CT use with similar rates of clinically important traumatic brain injuries after minor blunt head trauma compared with children without ventricular shunts.

Identifying children at very low risk of clinically important blunt abdominal injuries.

STUDY OBJECTIVE: We derive a prediction rule to identify children at very low risk for intra-abdominal injuries undergoing acute intervention and for whom computed tomography (CT) could be obviated. METHODS: We prospectively enrolled children with blunt torso trauma in 20 emergency departments. We used binary recursive partitioning to create a prediction rule to identify children at very low risk of intra-abdominal injuries undergoing acute intervention (therapeutic laparotomy, angiographic embolization, blood transfusion for abdominal hemorrhage, or intravenous fluid for ≥2 nights for pancreatic/gastrointestinal injuries). We considered only historical and physical examination variables with acceptable interrater reliability. RESULTS: We enrolled 12,044 children with a median age of 11.1 years (interquartile range 5.8, 15.1 years). Of the 761 (6.3%) children with intra-abdominal injuries, 203 (26.7%) received acute interventions. The prediction rule consisted of (in descending order of importance) no evidence of abdominal wall trauma or seat belt sign, Glasgow Coma Scale score greater than 13, no abdominal tenderness, no evidence of thoracic wall trauma, no complaints of abdominal pain, no decreased breath sounds, and no vomiting. The rule had a negative predictive value of 5,028 of 5,034 (99.9%; 95% confidence interval [CI] 99.7% to 100%), sensitivity of 197 of 203 (97%; 95% CI 94% to 99%), specificity of 5,028 of 11,841 (42.5%; 95% CI 41.6% to 43.4%), and negative likelihood ratio of 0.07 (95% CI 0.03 to 0.15). CONCLUSION: A prediction rule consisting of 7 patient history and physical examination findings, and without laboratory or ultrasonographic information, identifies children with blunt torso trauma who are at very low risk for intra-abdominal injury undergoing acute intervention. These findings require external validation before implementation.

MicroRNA-19a-3p Decreases with Age in Mice and Humans and Inhibits Osteoblast Senescence.

Aging is a major risk factor for most chronic diseases, including osteoporosis, and is characterized by an accumulation of senescent cells in various tissues. MicroRNAs (miRNAs) are critical regulators of bone aging and cellular senescence. Here, we report that miR-19a-3p decreases with age in bone samples from mice as well as in posterior iliac crest bone biopsies of younger versus older healthy women. miR-19a-3p also decreased in mouse bone marrow stromal cells following induction of senescence using etoposide, H2O2, or serial passaging. To explore the transcriptomic effects of miR-19a-3p, we performed RNA sequencing of mouse calvarial osteoblasts transfected with control or miR-19a-3p mimics and found that miR-19a-3p overexpression significantly altered the expression of various senescence, senescence-associated secretory phenotype-related, and proliferation genes. Specifically, miR-19a-3p overexpression in nonsenescent osteoblasts significantly suppressed p16 Ink4a and p21 Cip1 gene expression and increased their proliferative capacity. Finally, we established a novel senotherapeutic role for this miRNA by treating miR-19a-3p expressing cells with H2O2 to induce senescence. Interestingly, these cells exhibited lower p16 Ink4a and p21 Cip1 expression, increased proliferation-related gene expression, and reduced SA-ß-Gal+ cells. Our results thus establish that miR-19a-3p is a senescence-associated miRNA that decreases with age in mouse and human bones and is a potential senotherapeutic target for age-related bone loss. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.