RESUMO
INTRODUCTION: Enhanced Recovery After Surgery (ERAS®) protocols require multidisciplinary team engagement from healthcare professionals (HCPs), where limited studies exist on neonatal ERAS®protocols. Therefore, we aimed to capture perceptions of HCPs on facilitation and implementation of the neonatal ERAS®guideline. METHODS: 10 neonates were recruited. 13 HCPs involved in these patient's care were interviewed and 8 surveyed consisting of pediatric anesthesiologists, neonatologists, neonatal intensive care unit (NICU) registered nurses (RNs), and pediatric surgeons. Using a multi-methods design, recruitment, semi-structured interviews and surveys were conducted from May 17, 2021 to November 1, 2022. Data was coded using The Promoting Action on Research Implementation in Health Studies and then thematically analyzed. RESULTS: Interviews were conducted with 4 pediatric anesthesiologists, 4 neonatologists, 2 NICU RNs, and 3 pediatric surgeons and surveys with 1 pediatric anesthesiologist, 2 neonatologists, 3 NICU RNs, and 2 pediatric surgeons. From interviews, the top 3 facilitation strategies were utilization of: (1) multidisciplinary guideline champions, (2) reminders and education, and (3) results to facilitate adherence. Incorporation of these strategies resulted in perceived: (1) stronger buy-in and engagement and (2) improved team communication, job satisfaction, care quality, and parental involvement. CONCLUSION: HCPs stressed the importance of guideline champions, reminders and education, and results distribution. Given implementation during the COVID-19 pandemic, awareness and education were mixed. Nonetheless, HCPs perceived improved buy-in and engagement, communication, job satisfaction, quality of care, and parental involvement. Incorporation of these strategies can promote successful ERAS® guideline facilitation and implementation and should be considered for future ERAS® projects. LEVEL OF EVIDENCE: IV.
RESUMO
The clinical success of combined androgen deprivation therapy (ADT) and radiotherapy (RT) in prostate cancer created interest in understanding the mechanistic links between androgen receptor (AR) signaling and the DNA damage response (DDR). Convergent data have led to a model where AR both regulates, and is regulated by, the DDR. Integral to this model is that the AR regulates the transcription of DDR genes both at a steady state and in response to ionizing radiation (IR). In this study, we sought to determine which immediate transcriptional changes are induced by IR in an AR-dependent manner. Using PRO-seq to quantify changes in nascent RNA transcription in response to IR, the AR antagonist enzalutamide, or the combination of the two, we find that enzalutamide treatment significantly decreased expression of canonical AR target genes but had no effect on DDR gene sets in prostate cancer cells. Surprisingly, we also found that the AR is not a primary regulator of DDR genes either in response to IR or at a steady state in asynchronously growing prostate cancer cells. IMPLICATIONS: Our data indicate that the clinical benefit of combining ADT with RT is not due to direct AR regulation of DDR gene transcription, and that the field needs to consider alternative mechanisms for this clinical benefit.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Antagonistas de Androgênios/farmacologia , Linhagem Celular Tumoral , Dano ao DNA , Neoplasias de Próstata Resistentes à Castração/genéticaRESUMO
Outbreaks of virulent and/or drug-resistant bacteria have a significant impact on human health and major economic consequences. Genomic islands (GIs; defined as clusters of genes of probable horizontal origin) are of high interest because they disproportionately encode virulence factors, some antimicrobial-resistance (AMR) genes, and other adaptations of medical or environmental interest. While microbial genome sequencing has become rapid and inexpensive, current computational methods for GI analysis are not amenable for rapid, accurate, user-friendly and scalable comparative analysis of sets of related genomes. To help fill this gap, we have developed IslandCompare, an open-source computational pipeline for GI prediction and comparison across several to hundreds of bacterial genomes. A dynamic and interactive visualization strategy displays a bacterial core-genome phylogeny, with bacterial genomes linearly displayed at the phylogenetic tree leaves. Genomes are overlaid with GI predictions and AMR determinants from the Comprehensive Antibiotic Resistance Database (CARD), and regions of similarity between the genomes are also displayed. GI predictions are performed using Sigi-HMM and IslandPath-DIMOB, the two most precise GI prediction tools based on nucleotide composition biases, as well as a novel blast-based consistency step to improve cross-genome prediction consistency. GIs across genomes sharing sequence similarity are grouped into clusters, further aiding comparative analysis and visualization of acquisition and loss of mobile GIs in specific sub-clades. IslandCompare is an open-source software that is containerized for local use, plus available via a user-friendly, web-based interface to allow direct use by bioinformaticians, biologists and clinicians (at https://islandcompare.ca).
Assuntos
Genoma Bacteriano , Ilhas Genômicas , Bactérias/genética , Surtos de Doenças , Ilhas Genômicas/genética , Humanos , FilogeniaRESUMO
ABSTRACT: This study describes the minimum incidence of pediatric complex regional pain syndrome (CRPS), clinical features, and treatments recommended by pediatricians and pain clinics in Canada. Participants in the Canadian Paediatric Surveillance Program reported new cases of CRPS aged 2 to 18 years monthly and completed a detailed case reporting questionnaire from September 2017 to August 2019. Descriptive analysis was completed, and the annual incidence of CRPS by sex and age groupings was estimated. A total of 198 cases were reported to the Canadian Paediatric Surveillance Program, and 168 (84.8%) met the case definition. The minimum Canadian incidence of CRPS is estimated at 1.14/100,000 (95% confidence interval 0.93-1.35/100,000) children per year. Incidence was highest among girls 12 years and older (3.10, 95% confidence interval 2.76-3.44/100,000). The mean age of CRPS diagnosis was 12.2 years (SD = 2.4), with the mean time from symptom onset to diagnosis of 5.6 months (SD = 9.9) and no known inciting event for 19.6% of cases. Most cases had lower limb involvement (79.8%). Nonsteroidal anti-inflammatory drugs (82.7%) and acetaminophen (66.0%) were prescribed more commonly than antiepileptic drugs (52.3%) and antidepressants (32.0%). Referrals most commonly included physical therapy (83.3%) and multidisciplinary pain clinics (72.6%); a small number of patients withdrew from treatment because of pain exacerbation (5.3%). Pain education was recommended for only 65.6% of cases. Treatment variability highlights the need for empiric data to support treatment of pediatric CRPS and development of treatment consensus guidelines.
Assuntos
Síndromes da Dor Regional Complexa , Adolescente , Canadá/epidemiologia , Criança , Pré-Escolar , Síndromes da Dor Regional Complexa/diagnóstico , Síndromes da Dor Regional Complexa/epidemiologia , Feminino , Humanos , Incidência , Dor , Medição da DorRESUMO
OBJECTIVE: To evaluate the development process and clinical impact of implementing a standardized perioperative clinical care pathway for cleft palate repair. DESIGN: Medical records of patients undergoing primary cleft palate repair prior to pathway implementation were retrospectively reviewed as a historical control group (N = 40). The historical cohort was compared to a prospectively collected group of patients who were treated according to the pathway (N = 40). PATIENTS: Healthy, nonsyndromic infants undergoing primary cleft palate repair at a tertiary care pediatric hospital. INTERVENTIONS: A novel, standardized pathway was created through an iterative process, combining literature review with expert opinion and discussions with institutional stakeholders. The pathway integrated multimodal analgesia throughout the perioperative course and included intraoperative bilateral maxillary nerve blocks. Perioperative protocols for preoperative fasting, case timing, antiemetics, intravenous fluid management, and postoperative diet advancement were standardized. MAIN OUTCOME MEASURES: Primary outcomes include: (1) length of hospital stay, (2) cumulative opioid consumption, (3) oral intake postoperatively. RESULTS: Patients treated according to the pathway had shorter mean length of stay (31 vs 57 hours, P < .001), decreased cumulative morphine consumption (77 vs 727 µg/kg, P < .001), shorter time to initiate oral intake (9.3 vs 22 hours, P = .01), and greater volume of oral intake in first 24 hours postoperatively (379 vs 171 mL, P < .001). There were no differences in total anesthesia time, total surgical time, or complication rates between the control and treatment groups. CONCLUSIONS: Implementation of a standardized perioperative clinical care pathway for primary cleft palate repair is safe, feasible, and associated with reduced length of stay, reduced opioid consumption, and improved oral intake postoperatively.
Assuntos
Fissura Palatina , Analgésicos Opioides , Criança , Fissura Palatina/cirurgia , Procedimentos Clínicos , Humanos , Lactente , Assistência Perioperatória , Estudos RetrospectivosRESUMO
This paper develops a choice-theoretic equilibrium model of the labor market in the presence of a pandemic. It includes heterogeneity in productivity, age and the ability to work from home. Worker and firm behavior changes in the presence of the virus, which itself has equilibrium consequences for the infection rate. The model is calibrated to the UK and counterfactual lockdown measures are evaluated. We find a different response in both the evolution of the virus and the labor market with different lockdown policies. A laissez-faire approach results in lives lost and acts as negative shock to the economy. A lockdown policy, absent any other intervention, will reduce the lives lost but increase the economic burden. Consistent with recent evidence, we find that the economic costs from lockdown are most felt by those earning the least. Finally, we introduce a job retention scheme as implemented by the UK Government and find that it spreads the economic hardship more equitably.
RESUMO
Head and neck cancer is the sixth most common cancer worldwide with a 5-year survival of only 65%. Targeting compensatory signaling pathways may improve therapeutic responses and combat resistance. Utilizing reverse phase protein arrays (RPPA) to assess the proteome and explore mechanisms of synergistic growth inhibition in HNSCC cell lines treated with IGF1R and Src inhibitors, BMS754807 and dasatinib, respectively, we identified focal adhesion signaling as a critical node. Focal Adhesion Kinase (FAK) and Paxillin phosphorylation were decreased as early as 15 min after treatment, and treatment with a FAK inhibitor, PF-562,271, was sufficient to decrease viability in vitro. Treatment of 3D spheroids demonstrated robust cytotoxicity suggesting that the combination of BMS754807 and dasatinib is effective in multiple experimental models. Furthermore, treatment with BMS754807 and dasatinib significantly decreased cell motility, migration, and invasion in multiple HNSCC cell lines. Most strikingly, treatment with BMS754807 and dasatinib, or a FAK inhibitor alone, significantly increased cleaved-PARP in human ex-vivo HNSCC patient tissues demonstrating a potential clinical utility for targeting FAK or the combined targeting of the IGF1R with Src. This ex-vivo result further confirms FAK as a vital signaling node of this combinatorial treatment and demonstrates therapeutic potential for targeting FAK in HNSCC patients.
Assuntos
Dasatinibe/farmacologia , Quinase 1 de Adesão Focal/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Indóis/farmacologia , Pirazóis/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Sulfonamidas/farmacologia , Triazinas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Paxilina/metabolismo , Fosforilação/efeitos dos fármacos , Análise Serial de Proteínas , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológicoRESUMO
OBJECTIVE: This study examined the impact of a humanoid robot (MEDi®) programmed to teach deep breathing as a coping strategy, on children's pain and fear as primary and secondary outcomes, respectively, during intravenous (IV) line placement. The completion of IV induction was also examined as an exploratory outcome. METHODS: In this randomized controlled, two-armed trial, 137 children (4-12 years) were recruited in Short Stay Surgery at a tertiary pediatric hospital. Patients were randomly assigned to standard care (SC) with Ametop© only (N = 60) or SC and robot-facilitated intervention (N = 59) before induction. Pain and fear before, during, and after IV insertion were rated by patients and observers. RESULTS: No significant differences were found between groups and there were no changes over time for pain or fear (ps > .05). Exploratory analyses show that patients in the MEDi® group were 5.04 times more likely to complete IV induction, compared to SC, Fisher's exact test: X2 (1) = 4.85, p = .04, φc = 0.22, odds ratio = 5.04, 95% CI [1.06, 24.00]. CONCLUSION: This study was the first to examine children's IV induction experience when provided MEDi® support. Reasons for nonsignificance, limitations, and research suggestions were made.
Assuntos
Robótica , Adaptação Psicológica , Criança , Humanos , Dor , Manejo da Dor , Medição da DorAssuntos
Nervo Femoral , Bloqueio Nervoso , Humanos , Músculo Esquelético , Coxa da Perna , VoluntáriosRESUMO
PURPOSE: Enteral access via nasogastric tube (NGT) placement can be essential in the provision of care in pediatric patients. Methods exist to confirm correct placement with success rates between 80% and 85%. Radiographic confirmation remains the "gold-standard," however; it exposes patients to ionizing radiation and fails to provide "real-time" information. In this study, we determined the feasibility of using sonography to assist in the placement of NGT insertions in pediatric patients that have difficulty cooperating. METHODS: Thirty patients requiring NGT placement were stratified into three age groups. Upon NGT insertion, transverse and longitudinal ultrasound images were acquired to visualize tube progression through the esophagus. Subsequently, a focused ultrasonographic exam of the gastric antrum and body were performed. If amenable, an air bolus (1 mL/kg) was injected in the stomach if the NGT was not directly visualized. Following intubation, standard guidelines for NGT position confirmation were performed. RESULTS: The NGT was visualized in all esophageal views and 52% of gastric views. Subgroup analysis showed that successful visualization of tube placement in the stomach ranged from 40% (7-18 years) to 70% (3-6 years). Eighty percentage of air boluses injected were visualized. CONCLUSION: The use of ultrasonography may assist NGT placement in pediatric patients and reduce the incidence of suboptimal placement during insertion. We demonstrated successful NGT visualization through the esophagus regardless of age. NGT visualization in the stomach was challenging; however, injection of an air bolus may improve visualization. Further studies are required to improve the success rate of obtaining gastric views of the NGT.
Assuntos
Intubação Gastrointestinal/métodos , Criança , Esôfago/diagnóstico por imagem , Feminino , Humanos , Masculino , Estômago/diagnóstico por imagem , UltrassonografiaRESUMO
âPURPOSE: Suprazygomatic maxillary nerve blocks (SMB) are used in adult and pediatric patients to provide analgesia for midface surgery and chronic maxillofacial pain syndromes. The ultrasound-guided SMB technique ensures visualisation of the needle tip, avoidance of the maxillary artery and confirmation of local anesthetic spread. The goal of this study was to correctly identify SMB sonoanatomical landmarks to ensure the nerve block is performed safely and effectively. METHODS: Following an ultrasound-guided SMB with dye injection on 2 embalmed cadavers, pre-tragal face-lift style incision with a full thickness flap dissection was performed allowing accurate visualization of the bony landmarks being used for sonography and identification of the location of the injected dye. RESULTS: This study identifies the correct sonoanatomic landmarks as the maxilla and the coronoid process of the mandible which suggests that the block needle tip and local anesthetic injection are within the infratemporal fossa as opposed to the previously reported pterygopalatine fossa. CONCLUSION: An improved understanding of the sonoanatomy will aid clinicians who are learning, performing and teaching the ultrasound-guided suprazygomatic approach to the maxillary nerve block.
Assuntos
Anestesia por Condução , Bloqueio Nervoso , Adulto , Cadáver , Criança , Humanos , Nervo Maxilar/anatomia & histologia , Nervo Maxilar/diagnóstico por imagem , Ultrassonografia , Ultrassonografia de IntervençãoAssuntos
Extubação , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Aerossóis , Betacoronavirus , COVID-19 , Intubação Intratraqueal , SARS-CoV-2RESUMO
BACKGROUND: Surgical correction of undescended testes is a common surgical procedure which can be performed via a two-incision technique or a single high scrotal incision (Bianchi technique). The Bianchi technique requires less surgical time and may be associated with less pain in the initial postoperative period, however it has been adopted slowly due to a lack of familiarity and perceived technical challenges of the technique. Traditionally postoperative orchiopexy pain is managed with a caudal or ilioinguinal/iliohypogastric nerve block. As urologists at our site adopted the Bianchi technique, the anesthesiologists stopped performing caudals or ilioinguinal/iliohypogastric nerve blocks as local infiltration appeared sufficient. Therefore, this quality improvement (QI) project endeavoured to assess Alberta Children's Hospital's care pathway in its effectiveness to control pain in the first 24 h following pediatric orchiopexy using the Bianchi technique. METHODS: We completed a prospective QI project examining a care pathway for patients undergoing orchiopexy using the Bianchi technique. Eligible patients were healthy and aged 6 months to 12 years. A multimodal analgesic approach including local anesthetic surgical infiltration was used. Pain scores (FLACC) were recorded for up to 2 h postoperatively and a PPPM was completed at 24 h postoperatively. RESULTS: Sixty-four patients were included in the final analysis. The median discharge FLACC score was 0 (range 0-2) (Table 2). Median intraoperative morphine administered was 0.09 mg/kg with no significant correlations between the amount of morphine administered and postoperative pain measures. Median PPPM scores were 4 and 3.5 for unilateral and bilateral procedures, respectively. CONCLUSIONS: We have demonstrated that orchiopexies repaired using the Bianchi technique following the care pathway established at Alberta Children's Hospital are associated with minimal pain scores. Our QI project suggests that combining a Bianchi technique with a simple multimodal analgesic approach including local infiltration, negates the need for regional anesthesia techniques, yet still provides adequate analgesia.
Assuntos
Criptorquidismo , Orquidopexia , Criança , Criptorquidismo/cirurgia , Humanos , Masculino , Manejo da Dor , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/prevenção & controle , Estudos Prospectivos , Melhoria de QualidadeAssuntos
Extubação , Infecções por Coronavirus , Pandemias , Plásticos , Pneumonia Viral , Aerossóis , Betacoronavirus , COVID-19 , Humanos , SARS-CoV-2RESUMO
EGFR inhibitors have shown poor efficacy in head and neck squamous cell carcinoma (HNSCC) with demonstrated involvement of the insulin-like growth factor-1 receptor (IGF1R) in resistance to EGFR inhibition. IGF1R activates the PI3K-Akt pathway, which phosphorylates proline-rich Akt substrate of 40 kDa (PRAS40) to cease mTOR inhibition resulting in increased mTOR signaling. Proliferation assays separated six HNSCC cell lines into two groups: sensitive to EGFR inhibition or resistant; all sensitive cell lines demonstrated reduced sensitivity to EGFR inhibition upon IGF1R activation. Reverse phase protein microarray analysis and immunoblot identified a correlation between increased PRAS40 phosphorylation and IGFR-mediated resistance to EGFR inhibition. In sensitive cell lines, PRAS40 phosphorylation decreased 44%-80% with EGFR inhibition and was restored to 98%-196% of control by IGF1R activation, while phosphorylation was unaffected in resistant cell lines. Possible involvement of mTOR in this resistance mechanism was demonstrated through a similar pattern of p70S6K phosphorylation. However, addition of temsirolimus, an mTORC1 inhibitor, was insufficient to overcome IGF1R-mediated resistance and suggested an alternative mechanism. Forkhead box O3a (FOXO3a), which has been reported to complex with PRAS40 in the cytoplasm, demonstrated a 6-fold increase in nuclear to cytoplasmic ratio upon EGFR inhibition that was eliminated with concurrent IGF1R activation. Transcription of FOXO3a-regulated TRAIL and PTEN-induced putative kinase-1 (PINK1) was increased with EGFR inhibition in sensitive cell lines; this effect was diminished with IGF1R stimulation. IMPLICATIONS: These data suggest PRAS40 may play an important role in IGF1R-based therapeutic resistance to EGFR inhibition, and this likely occurs via inhibition of FOXO3a-mediated proapoptotic gene transcription.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fosforilação , Transdução de Sinais , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismoAssuntos
Infecções por Coronavirus , Pneumonia Viral , Extubação , Betacoronavirus , COVID-19 , Humanos , Pandemias , SARS-CoV-2RESUMO
Tauopathies are neurodegenerative diseases that affect millions of people worldwide including those with Alzheimer's disease. While many efforts have focused on understanding the role of tau protein in neurodegeneration, there has been little done to systematically analyze and study the structures within tau's encoding RNA and their connection to disease pathology. Knowledge of RNA structure can provide insights into disease mechanisms and how to affect protein production for therapeutic benefit. Using computational methods based on thermodynamic stability and evolutionary conservation, we identified structures throughout the tau pre-mRNA, especially at exon-intron junctions and within the 5' and 3' untranslated regions (UTRs). In particular, structures were identified at twenty exon-intron junctions. The 5' UTR contains one structured region, which lies within a known internal ribosome entry site. The 3' UTR contains eight structured regions, including one that contains a polyadenylation signal. A series of functional experiments were carried out to assess the effects of mutations associated with mis-regulation of alternative splicing of exon 10 and to identify regions of the 3' UTR that contain cis-regulatory elements. These studies defined novel structural regions within the mRNA that affect stability and pre-mRNA splicing and may lead to new therapeutic targets for treating tau-associated diseases.
Assuntos
Precursores de RNA/química , RNA Mensageiro/genética , Tauopatias/genética , Proteínas tau/genética , Regiões 3' não Traduzidas/genética , Processamento Alternativo/genética , Doença de Alzheimer , Éxons/genética , Humanos , Íntrons/genética , Mutação , Conformação de Ácido Nucleico , Poliadenilação/genética , Precursores de RNA/genética , RNA Mensageiro/química , Tauopatias/patologia , Proteínas tau/químicaRESUMO
ADP-ribosylation is a posttranslational modification generated by members of the superfamily of ADP-ribosyltransferases, known as the Parp enzymes. Depending on the superfamily member, Parp enzymes can mono- or poly-ADP-ribosylate a protein substrate. Parp superfamily members confer regulation to a variety of biological processes that include cell signaling, DNA repair, transcription, and stress responses. Here, we describe biochemical methods for detection of ADP-ribose conjugated to the androgen receptor (AR) using the archaeal macrodomain, AF1521, from Archaeoglobus fulgidus. The utility of AF1521 is based on its highly selective recognition of ADP-ribose conjugated to protein. AF1521 immobilized on beads can be used to enrich for ADP-ribosylated proteins, which in our application results in recovery of ADP-ribosylated AR from prostate cancer cell extracts. We engineered tandem AF1521 macrodomains and found this improves the recovery of ADP-ribosylated AR under native conditions, and it enabled development of an assay for detection of ADP-ribosylation on blots. Thus, AF1521 can be used to query ADP-ribosylation of protein under both native and denaturing conditions. Our assays should prove useful for understanding how ADP-ribosylation regulates AR function.