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The monocyte-macrophage system plays an important role in phagocytosis of pathogens and cellular debris following infection or tissue injury in several pathophysiological conditions. We examined ENaC/ASIC subunit transcript expression and the importance of select subunits in migration of bone marrow derived monocytes (freshly isolated) and macrophages (monocytes differentiated in culture). We also examined the effect of select subunit deletion on macrophage phenotype. BM monocytes were harvested from the femurs of male and female WT and KO mice (6-12 weeks of age). Our results show that α, ß, γENaC, and ASIC1-5 transcripts are expressed in BM macrophages and monocytes to varying degrees. At least αENaC, ßENaC, and ASIC2 subunits contribute to chemotactic migration responses in BM monocyte-macrophages. Polarization markers (CD86, soluble TNFα) in BM macrophages from mice lacking ASIC2a plus ßENaC were shifted towards the M1 phenotype. Furthermore, select M1 phenotypic markers were recovered with rescue of ßENaC or ASIC2. Taken together, these data suggest that ßENaC and ASIC2 play an important role in BM macrophage migration and loss of ßENaC and/or ASIC2 partially polarizes macrophages to the M1 phenotype. Thus, targeting ENaC/ASIC expression in BM macrophages may regulate their ability to migrate to sites of injury.
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Canais Iônicos Sensíveis a Ácido , Quimiotaxia , Canais Epiteliais de Sódio , Macrófagos , Monócitos , Animais , Canais Epiteliais de Sódio/metabolismo , Canais Epiteliais de Sódio/genética , Macrófagos/metabolismo , Masculino , Camundongos , Canais Iônicos Sensíveis a Ácido/metabolismo , Canais Iônicos Sensíveis a Ácido/genética , Feminino , Monócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células da Medula Óssea/metabolismo , Células CultivadasRESUMO
Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm.
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Consenso , Glioma , Mutação , Proteínas Proto-Oncogênicas B-raf , Adolescente , Criança , Feminino , Humanos , Masculino , Adulto Jovem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamento farmacológico , Canadá , Glioma/genética , Glioma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Introduction: Threaded conical centrifuge tubes are ubiquitous in biological laboratories and are frequently used for the storage/transport of potentially biohazardous samples. However, limited data are available on how frequently and from where these tubes leak. These data are valuable for laboratory biorisk management and to inform future studies on risks arising from the routine use of laboratory consumables. Methods: The frequency of leaks from threaded conical centrifuge tubes was tested using a Glo Germ solution as a tracer. Conical tubes (15 and 50 mL) from several brands were filled, inverted, and placed on their side on the benchtop. After 1 h, the presence or absence of leaks on the benchtop surface, tube threads, and exterior was recorded. Results: We observed that liquid leaked out of tubes that were apparently properly threaded in 2% of 15 mL tubes (confidence interval [95% CI] 1.4-2.6) and 1.4% of 50 mL tubes (95% CI 0.2-1.5). After opening, liquid was found on the threads on the outside of the tube in 20% of 15 mL tubes (95% CI 10-31) and 14% of 50 mL tubes (95% CI 1-28). We did not find sufficient evidence that differences in leak rates among brands were practically significant. Conclusions: The fact that leaks were not uncommonly observed from conical centrifuge tubes suggests that mitigations for any hazard posed by a leak should be a component of every biorisk management strategy for protocols involving the manipulation of hazardous substances in these tubes. Further research should be conducted on other activities that could cause tubes to leak (such as centrifugation or vortexing) and should be completed to understand the risks associated with this consumable. Research into the costs and benefits of mitigating the risk of leaks from conical tubes is recommended.
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BACKGROUND: Cerebellar mutism (CM) is characterized by a significant loss of speech in children following posterior fossa (PF) surgery. The biological origin of CM remains unclear and is the subject of ongoing debate. Significant recovery from CM is less likely than previously described despite rigorous multidisciplinary neuro-rehabilitational efforts. METHODS: A national multi-centered retrospective review of all children undergoing PF resection in four midsized Canadian academic pediatric institutions was undertaken. Patient, tumor and surgical factors associated with the post-operative development of CM were reviewed. Retrospective identification of PF surgery patients including those developing and those that did not (internal control). RESULTS: The study identified 258 patients across the 4 centers between 2010 and 2020 (mean age 6.73 years; 42.2% female). Overall, CM was experienced in 19.5% of patients (N = 50). Amongst children who developed CM histopathology included medulloblastoma (35.7%), pilocytic astrocytoma (32.6%) and ependymoma (17.1%). Intraoperative impression of adherence to the floor of the 4th ventricle was positive in 36.8%. Intraoperative abrupt changes in blood pressure and/or heart rate were identified in 19.4% and 17.8% of cases. The clinical resolution of CM was rated to be complete, significant resolution, slight improvement, no improvement and deterioration in 56.0%, 8.0%, 20.0%, 14.0% and 2.0%, respectively. In the cohort of children who experienced post-operative CM as compared to their no-CM counterpart, proportionally more tumors were felt to be adherent to the floor of the 4th ventricle (56.0% vs 49.5%), intraoperative extent of resection was a GTR (74% vs 68.8%) and changes in heart rate were noted (≥ 20% from baseline) (26.0% vs 15.9%). However, a multiple regression analysis identified only abrupt changes in HR (OR 5.97, CI (1.53, 23.1), p = 0.01) to be significantly associated with the development of post-operative CM. CONCLUSION: As a devastating surgical complication after posterior fossa tumor surgery with variable clinical course, identifying and understanding the operative cues and revising intraoperative plans that optimizes the child's neurooncological and clinical outcome are essential.
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Neoplasias Cerebelares , Neoplasias Infratentoriais , Meduloblastoma , Mutismo , Humanos , Criança , Feminino , Masculino , Estudos Retrospectivos , Mutismo/etiologia , Complicações Pós-Operatórias , Canadá , Neoplasias Infratentoriais/cirurgia , Meduloblastoma/cirurgia , Síndrome , Neoplasias Cerebelares/cirurgiaRESUMO
BACKGROUND: Cancer predisposition syndromes (CPSs) are responsible for at least 10% of cancer diagnoses in children and adolescents, most of which are not clinically recognised prior to cancer diagnosis. A variety of clinical screening guidelines are used in healthcare settings to help clinicians detect patients who have a higher likelihood of having a CPS. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) is an electronic health decision support tool that uses algorithms to help clinicians determine if a child/adolescent diagnosed with cancer should be referred to genetics for a CPS evaluation. METHODS: This study assessed MIPOGG's performance in identifying Li-Fraumeni, DICER1, Constitutional mismatch repair deficiency and Gorlin (nevoid basal cell carcinoma) syndromes in a retrospective series of 84 children diagnosed with cancer and one of these four CPSs in Canadian hospitals over an 18-year period. RESULTS: MIPOGG detected 82 of 83 (98.8%) evaluable patients with any one of these four genetic conditions and demonstrated an appropriate rationale for suggesting CPS evaluation. When compared with syndrome-specific clinical screening criteria, MIPOGG's ability to correctly identify children with any of the four CPSs was equivalent to, or outperformed, existing clinical criteria respective to each CPS. CONCLUSION: This study adds evidence that MIPOGG is an appropriate tool for CPS screening in clinical practice. MIPOGG's strength is that it starts with a specific cancer diagnosis and incorporates criteria relevant for associated CPSs, making MIPOGG a more universally accessible diagnostic adjunct that does not require in-depth knowledge of each CPS.
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Sistemas de Apoio a Decisões Clínicas , Síndromes Neoplásicas Hereditárias , Criança , Humanos , Algoritmos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Estudos RetrospectivosRESUMO
Introduction: Snap-cap microcentrifuge tubes are ubiquitous in biological laboratories. However, limited data are available on how frequently splashes occur when opening them. These data would be valuable for biorisk management in the laboratory. Methods: The frequency of splashes from opening snap-cap tubes using four different methods was tested. The splash frequency for each method was measured on the benchtop surface and on the experimenter's gloves and smock, using a Glo Germ solution as a tracer. Results: Splashes occurred very frequently when opening microcentrifuge snap-cap tubes, no matter which method was used to open the tube. The highest rate of splashes on all surfaces was observed with the one-handed (OH) opening method compared with two-handed methods. Across all methods, the highest rate of splashes was observed on the opener's gloves (70-97%) compared with the benchtop (2-40%) or the body of the researcher (0-7%). Conclusions: All tube opening methods we studied frequently caused splashes, with the OH method being the most error-prone but no two-handed method being clearly superior to any other. In addition to posing an exposure risk to laboratory personnel, experimental repeatability may be affected due to loss of volume when using snap-cap tubes. The rate of splashes underscores the importance of secondary containment, personal protective equipment, and good protocols for decontamination. When working with especially hazardous materials, alternatives to snap-cap tubes (such as screw cap tubes) should be strongly considered. Future studies can examine other methods of opening snap-cap tubes to determine whether a truly safe method exists.
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ABSTRACT: Fleming, A, Walker, M, Armitage, M, Connor, M, and Beato, M. A comparison of training and match play external load during a congested in-season period in English League 2 Football. J Strength Cond Res 37(9): e527-e534, 2023-This study aimed to investigate if external training load metrics differ between training days and match day (MD) during a period of fixture congestion and to verify if external load metrics vary based on playing positions. Training and MD data were collected in a part of the competition phase of the 2020-2021 season (6 weeks) in the English Football League 2 ( N = 20 players, mean ± SD s: age = 24.4 ± 4.7 years). Global Navigation Satellite System units (Catapult S7 Vector 10 Hz) were used to monitor external load metrics. The metrics were duration of training, total distance (TD), high-speed running distance (HSR), sprinting distance, relative intensity (m/min), total accelerations (TotAcc) (>3 m·s -2 ), and total decelerations (TotDec) (<-3 m·s -2 ). This study found that duration, TD, relative intensity, HSR distance, sprint distance, TotAcc, and TotDec were different ( p < 0.001, d = small to moderate ) between MD and match day minus two (MD-2) or match day minus one (MD-1); however, during match day minus four (MD-4), only relative intensity was significantly lower ( p < 0.001) compared with MD output. Therefore, MD-4 was the most demanding training session of the week (after the MD), and during MD-2 and MD-1, coaches decreased players' load to favor players' readiness. Moreover, this study found that MD and MD-1 resulted in statistically different values across several metrics between different playing positions (defenders < midfielders and strikers), whereas metrics in MD-4 and MD-2 were not statistically different, which highlights that in these sessions, players have similar external loads independently from their playing positions.
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Desempenho Atlético , Corrida , Futebol , Humanos , Adulto Jovem , Adulto , Estações do Ano , Sistemas de Informação GeográficaRESUMO
Arthropods are vectors for many pathogens that significantly harm human and animal health globally, and research into vector-borne diseases is of critical public health importance. Arthropods present unique risks for containment, and therefore insectary facilities are essential to the safe handling of arthropod-borne hazards. In 2018, the School of Life Sciences at Arizona State University (ASU) began the process to build a level 3 arthropod containment (ACL-3) facility. Even with the COVID-19 pandemic, it took more than 4 years for the insectary to be granted a Certificate of Occupancy. At the request of the ASU Environmental Health and Safety team, Gryphon Scientific, an independent team with biosafety and biological research expertise, studied the project lifecycle through the design, construction, and commissioning of the ACL-3 facility with the goal of identifying lessons learned from the delayed timeline. These lessons learned convey insight into best practices for assessing potential facility sites, anticipating challenges with retrofitted construction, preparing for commissioning, equipping the project team with necessary expertise and expectations, and supplementing the gaps in available containment guidance. Several unique mitigations designed by the ASU team to address research risks not specifically addressed in the American Committee of Medical Entomology Arthropod Containment Guidelines are also described. Completion of the ACL-3 insectary at ASU was delayed, but the team thoroughly assessed potential risks and enabled appropriate practices for the safe handling of arthropod vectors. These efforts will enhance future ACL-3 construction by helping to avoid similar setbacks and streamlining progress from concept to operation.
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Artrópodes , COVID-19 , Animais , Humanos , Pandemias/prevenção & controle , Vetores Artrópodes , Contenção de Riscos BiológicosRESUMO
BACKGROUND: Studies to date have yielded inconclusive results as to whether maternal medical history during pregnancy, and a child's early-life medical history contribute to the development of childhood brain tumours (CBTs). This study examined associations between maternal and childhood medical history and the risk of CBTs. METHODS: The Childhood Brain Tumour Epidemiology Study of Ontario (CBREO) examined children 0-15 years of age with newly diagnosed CBTs from 1997 to 2003. Multivariable logistic regression analysis determined associations for prenatal medications and childhood medical history, adjusted for child's demographics, and maternal education. Analyses were stratified by histology. A latency period analysis was conducted using 12- and 24-month lead times. RESULTS: Maternal intake of immunosuppressants during the prenatal period was significantly associated with glial tumours (OR 2.73, 95% CI 1.17-6.39). Childhood intake of anti-epileptics was significantly associated with CBTs overall, after accounting for 12-month (OR 8.51, 95% CI 3.35-21.63) and 24-month (OR 6.04, 95% CI 2.06-17.70) lead time before diagnosis. No associations for other medications were found. CONCLUSIONS: This study underscores the need to examine potential carcinogenic effects of the medication classes highlighted and of the indication of medication use. Despite possible reverse causality, increased CBT surveillance for children with epilepsy might be warranted.
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Neoplasias Encefálicas , Efeitos Tardios da Exposição Pré-Natal , Criança , Feminino , Gravidez , Humanos , Estudos de Casos e Controles , Ontário/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Família , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/etiologia , Fatores de RiscoRESUMO
PURPOSE: To determine whether intraoperative adjunctive EVD placement in patients with a posterior fossa tumor (PFT) led to improved surgical, radiographic, and clinical outcomes compared to those who did not receive an EVD. METHODS: Patients were grouped as those who underwent routine intraoperative adjunctive EVD insertion and those who did not at time of PFT resection. Patients who pre-operatively required a clinically indicated EVD insertion were excluded. Comparative analyses between both groups were conducted to evaluate clinical, radiological, and pathological outcomes. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were computed for post-operative outcomes. RESULTS: Fifty-five selected patients were included, 15 who had an EVD placed at the time of PFT resection surgery, and 40 who did not. Children without an EVD did not experience a higher rate of complications or poorer post-operative outcomes compared to those with an EVD placed during resection surgery. There was no significant difference in the degree of gross total resection (p = 0.129), post-operative CSF leak (p = 1.000), and post-operative hemorrhage (p = 0.554) between those with an EVD and those without. The frequency of new cranial nerve deficits post-operatively was higher in those with an EVD (40%) compared to those without (3%, p = 0.001). There was a trend towards more frequently observed post-operative hydrocephalus in the EVD group (p = 0.057). CONCLUSION: The routine use of EVD as an intraoperative adjunct in clinically stable pediatric patients with posterior fossa tumors and hydrocephalus may not be associated with improved radiological or clinical outcomes.
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Neoplasias Encefálicas , Hidrocefalia , Neoplasias Infratentoriais , Humanos , Criança , Estudos Retrospectivos , Ventriculostomia/efeitos adversos , Complicações Pós-Operatórias/etiologia , Neoplasias Encefálicas/cirurgia , Neoplasias Infratentoriais/complicações , Neoplasias Infratentoriais/diagnóstico por imagem , Neoplasias Infratentoriais/cirurgia , Hidrocefalia/etiologia , Hidrocefalia/cirurgia , Drenagem/efeitos adversosRESUMO
The present study investigated the post-activation performance enhancement (PAPE) of isokinetic quadriceps and hamstrings torque after flywheel (FW)-squat vs. FW-deadlift in comparison to a control condition. Fifteen male athletes were enrolled in this randomised, crossover study. Each protocol consisted of 3 sets of 6 repetitions, with an inertial load of 0.029 kg.m2. Isokinetic quadriceps (knee extension) and hamstrings (knee flexion) concentric peak torque (60º/s) and hamstring eccentric peak torque (-60º/s) were measured 5 min after experimental or control conditions. A significant condition (PAPE) effect was reported (f = 4.067, p = 0.008) for isokinetic hamstrings eccentric peak torque following FW-squat and FW-deadlift, but no significant differences were found for quadriceps and hamstrings concentric peak torques. The significant difference averaged 14 Nm between FW-squat vs. control (95% CI: 2, 28; d = 0.75, moderate; p = 0.033), and 13 Nm between FW-deadlift vs. control (95% CI: 1, 25; d = 0.68, moderate; p = 0.038). This study reported that both FW-squat and FW-deadlift exercises are equivalently capable of generating PAPE of isokinetic hamstrings eccentric torque. Practitioners may use these findings to inform strength and power development during complex training sessions consisting of flywheel-based exercises prior to a sport-specific task.
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Atletas , Extremidade Inferior , Humanos , Masculino , Torque , Estudos Cross-Over , Fenômenos Biomecânicos , Força Muscular/fisiologia , Músculo Esquelético/fisiologiaRESUMO
BACKGROUND: Juvenile pilocytic astrocytoma (JPA) typically follows an indolent clinical course. The first-line treatment for most JPAs is surgical resection. However, a gross total resection may not be feasible for deep-seated lesions and/or infiltrative tumors, leading to multimodal treatment approaches that may be complicated by patient age and tumor location. Despite the prevalence of pediatric JPAs, there is no single approach to treating progressive disease. METHODS: We investigated the multifaceted management of progressive JPAs through a retrospective analysis of JPAs treated at a single center over an 18-year period (1998-2016). All cases were categorized according to location, whether supratentorial or infratentorial, and for each case we calculated the number of interventions and the time between interventions. RESULTS: We identified a total of 40 JPAs, (11 supratentorial, 29 infratentorial). Total number of interventions among all supratentorial JPA patients was 21 (average 2 interventions/patient). The total number of interventions among infratentorial JPAs was 40 (average 1.4 interventions/patient). CONCLUSIONS: Treatment of progressive JPA is variable and may require numerous surgeries and adjuvant therapies.
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Astrocitoma , Neoplasias Encefálicas , Humanos , Criança , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/patologia , Estudos Retrospectivos , Astrocitoma/cirurgia , Astrocitoma/patologiaRESUMO
Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identify binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.
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Neoplasias Encefálicas , Neoplasias Cerebelares , Meduloblastoma , Animais , Camundongos , Humanos , Proteômica , Meduloblastoma/genética , Proteínas de Ligação a RNA/genética , Neoplasias Cerebelares/genética , Proteínas do Tecido NervosoRESUMO
Background: Approximately 30% of childhood cancer survivors (CCSs) will develop chronic kidney disease (CKD) or hypertension 15 to 20 years after treatment ends. The incidence of CKD and hypertension in the 5-year window after cancer therapy is unknown. Moreover, extent of monitoring of CCS with CKD and associated complications in current practice is underexplored. To inform the development of new and existing care guidelines for CCS, the epidemiology and monitoring of CKD and hypertension in the early period following cancer therapy warrants further investigation. Objective: To describe the design and methods of the KIdney aNd blooD prESsure ouTcomes in Childhood Cancer Survivors study, which aims to evaluate the burden of late kidney and blood pressure outcomes in the first ~10 years after cancer therapy, the extent of appropriate screening and complications monitoring for CKD and hypertension, and whether patient, disease/treatment, or system factors are associated with these outcomes. Design: Two distinct, but related studies; a prospective cohort study and a retrospective cohort study. Setting: Five Ontario pediatric oncology centers. Patients: The prospective study will involve 500 CCS at high risk for these late effects due to cancer therapy, and the retrospective study involves 5,000 CCS ≤ 18 years old treated for cancer between January 2008 and December 2020. Measurements: Chronic kidney disease is defined as Estimated glomerular filtration rate <90 mL/min/1.73 m2 or albumin-to-creatinine ratio ≥ 3mg/mmol. Hypertension is defined by 2017 American Academy of Pediatrics guidelines. Methods: Prospective study: we aim to investigate CKD and hypertension prevalence and the extent to which they persist at 3- and 5-year follow-up in CCS after cancer therapy. We will collect detailed biologic and clinical data, calculate CKD and hypertension prevalence, and progression at 3- and 5-years post-therapy. Retrospective study: we aim to investigate CKD and hypertension monitoring using administrative and health record data. We will also investigate the validity of CKD and hypertension administrative definitions in this population and the incidence of CKD and hypertension in the first ~10 years post-cancer therapy. We will investigate whether patient-, disease/treatment-, or system-specific factors modify these associations in both studies. Limitations: Results from the prospective study may not be generalizable to non-high-risk CCS. The retrospective study is susceptible to surveillance bias. Conclusions: Our team and knowledge translation plan is engaging patient partners, researchers, knowledge users, and policy group representatives. Our work will address international priorities to improve CCS health, provide the evidence of new disease burden and practice gaps to improve CCS guidelines, implement and test revised guidelines, plan trials to reduce CKD and hypertension, and improve long-term CCS health.
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There has been a significant rise in the number of emergency department (ED) visits over the past 15 years despite the number of ED providers and treatment spaces remaining fixed (M. P. Lin et al., 2018). A hospital's need to quickly initiate care upon patient arrival is of paramount importance to combat these ED overcrowding trends. A teleprovider in triage (TPIT) program without a standardized operating protocol leads to significant provider practice variations and limits effectiveness of a TPIT program. The intention of this health care project was to reduce ED time metrics and reduce the number of patients who left before evaluation by implementing a standardized TPIT protocol. This standardization allowed for a more predictable experience for the patient and ED staff. This quality improvement project involved developing and implementing a standardized TPIT protocol to improve TPIT efficiency and throughput. Patient ED visit metrics were collected during the pre- and postimplementation periods to evaluate for any improvement in throughput due to the TPIT protocol. The TPIT advanced practice providers (APPs) showed significant improvement in knowledge following the TPIT protocol education with an increase in provider comfort (p < 0.05). Time spent by the TPIT provider on each patient encounter was reduced by 23%, demonstrating increased provider efficiency. Improvements in discharge lengths of stay (LOS) (p = 0.68) and room to discharge LOS (p < 0.05) were noted following the implementation of the TPIT protocol. CONCLUSIONS: The implementation of the TPIT protocol provided improvements in APP knowledge and understanding of the process while increasing provider efficiency. Improvements were identified in specific ED patient metrics demonstrating the significance of the TPIT protocol on patient care.
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Telemedicina , Triagem , Humanos , Triagem/métodos , Melhoria de Qualidade , Serviço Hospitalar de Emergência , Tempo de Internação , Eficiência OrganizacionalRESUMO
Migration of monocytes-macrophages plays an important role in phagocytosis of pathogens and cellular debris in a variety of pathophysiological conditions. Although epithelial Na+ channels (ENaCs) are required for normal migratory responses in other cell types, their role in macrophage migration signaling is unknown. To address this possibility, we determined whether ENaC message is present in several peripheral blood monocyte cell populations and tissue-resident macrophages in healthy humans using the Human Protein Atlas database (www.proteinatlas.org) and the mouse monocyte cell line RAW 264.7 using RT-PCR. We then determined that selective ENaC inhibition with amiloride inhibited chemotactic migration (â¼50%), but not phagocytosis, of the mouse monocyte-macrophage cell line RAW 264.7. Furthermore, we generated a cell line stably expressing an NH2-terminal truncated αENaC to interrupt normal channel trafficking and found it suppressed migration. Prolonged exposure (48 h) of RAW 264.7 cells to proinflammatory cytokines interferon γ (IFNγ) and/or tumor necrosis factor α (TNFα) inhibited RAW 264.7 migration and abolished the amiloride (1 µM)-sensitive component of migration, a finding consistent with ENaC downregulation. To determine if proinflammatory cytokines regulate αENaC protein expression, cells were exposed to proinflammatory cytokines IFNγ (10 ng/mL, last 48 h) and TNFα (10 ng/mL, last 24 h). By Western blot analysis, we found whole cell αENaC protein is reduced ≥50%. Immunofluorescence demonstrated heterogeneous αENaC inhibition. Finally, we found that overnight exposure to amiloride stimulated morphological changes and increased polarization marker expression. Our findings suggest that ENaC may be a critical molecule in macrophage migration and polarization.
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Canais Epiteliais de Sódio , Fator de Necrose Tumoral alfa , Camundongos , Animais , Humanos , Canais Epiteliais de Sódio/genética , Canais Epiteliais de Sódio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Amilorida/farmacologia , Interferon gama/farmacologia , Interferon gama/metabolismo , Citocinas/metabolismo , Macrófagos/metabolismoRESUMO
A child had been followed since infancy by our multi-disciplinary neuro-oncology clinic with annual magnetic resonance imaging (MRI) under the presumed diagnosis of encephalocraniocutaneous lipomatosis (ECCL), with clinical features including nevus psiloliparus, scalp lipoma, nodular skin tag on and coloboma of the eyelid, cortical atrophy and meningeal angiomatosis. At the age of 4, she was found to have a large temporoparietal lesion causing elevated intracranial pressure requiring surgical resection. Histopathological exam of the tumor was suggestive of an intracranial sarcoma. Sequencing analysis of the tumor revealed mutations in DICER1, KRAS and TP53. Subsequent germline testing confirmed DICER1 syndrome and revealed an insignificant FGFR1 variant at a low frequency. Methylation profile of the tumor showed the tumor clustered most closely with sarcoma (rhabdomyosarcoma-like), confirming this tumor to be a primary DICER1-sarcoma. Compared to the previously reported cases, our unique case of primary DICER1-sarcoma also demonstrated neurofilament and chromogranin positivity, and genomic instability with loss of chromosome 4p, 4q, 8p, 11p, and 19p, as well as gains in chromosome 7p, 9p, 9q, 13q, and 15q on copy variant analysis. The detailed sequencing and methylation information discovered in this unique case of DICER1-sarcoma will hopefully help further our understanding of this rare and emerging entity.
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Proteínas Proto-Oncogênicas p21(ras) , Sarcoma , Criança , Cromograninas/genética , RNA Helicases DEAD-box/genética , Oftalmopatias , Feminino , Humanos , Lipomatose , Mutação , Síndromes Neurocutâneas , Proteínas Proto-Oncogênicas p21(ras)/genética , Ribonuclease III/genética , Sarcoma/diagnóstico , Sarcoma/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Multidisciplinary neuro-oncology clinics allow collaboration between various specialties and training levels. Building a tenable clinical research program based in the longitudinal dialogue and practice of collaborative clinicians and trainees can bridge clinical observations to research execution. However, forming a research team around a multidisciplinary clinic's activities is constrained by a lack of literature or guidelines. As well, challenges in sustaining team logistics, communication, and productivity can persist without a standardized team framework. This perspective discusses the state of research teams in clinical oncology, and uses experiences from the McMaster Pediatric Brain Tumour Study Group to guide those seeking to form a research team based on the collective activities and observations of a multidisciplinary clinic.