Can a second look improve the outcome of endoscopic choanal atresia repair?

PURPOSE: To evaluate the outcome of a routine postoperative endoscopic micro-debridement of granulation tissue after stentless transnasal endoscopic repair of choanal atresia (CA). METHODS: This prospective case series included congenital CA patients who underwent stentless transnasal endoscopic repair, followed by an endoscopic second look and micro-debridement of granulation tissue at 1-2 weeks post-repair. Patients were followed every three months for assessment of nasal airway symptoms and objective evaluation by flexible nasolaryngoscopy. RESULTS: Sixteen CA patients (8 bilateral and 8 unilateral) underwent surgical repair (12 primary and 4 revisions). The median  age was 13 days (range 1 day-6 months) in bilateral and 3 years  (range 7 months-15 years) in unilateral atresia. The mean follow-up was 1.5 years (range 1 year-3 years). In primary procedures, the obstruction was bony-membranous in 7 cases and bony in 5 cases. The mean interval time between the CA repair and re-examination was 10.75 days (range 6-18 days). Clinically significant neochoanal restenosis was not encountered. CONCLUSIONS: Re-examination under general anesthesia with endoscopic micro-debridement of granulation tissue is a safe, potentially effective adjunct when done during the proliferative phase of neochoanal wound healing. This procedure might help in maintaining neochoanal patency by remodeling tissue healing process. Large-scale, long-term cohort studies are imperative.

International pediatric otolaryngology group (IPOG) consensus on approach to aspiration.

OBJECTIVE: To provide recommendations for a comprehensive management approach for infants and children presenting with symptoms or signs of aspiration. METHODS: Three rounds of surveys were sent to authors from 23 institutions worldwide. The threshold for the critical level of agreement among respondents was set at 80 %. To develop the definition of "intractable aspiration," each author was first asked to define the condition. Second, each author was asked to complete a 5-point Likert scale to specify the level of agreement with the definition derived in the first step. RESULTS: Recommendations by the authors regarding the clinical presentation, diagnostic considerations, and medical and surgical management options for aspiration in children. CONCLUSION: Approach to pediatric aspiration is best achieved by implementing a multidisciplinary approach with a comprehensive investigation strategy and different treatment options.

Examining the Impact of Puberty on Primary Headache Disorders in Female Schoolchildren: A Cross-Sectional Study.

Introduction and aim Headaches are one of the most prevalent childhood disorders. Primary and secondary headaches are the two types of headaches affecting kids and teenagers. The three most typical primary headache forms are tension-type headaches (TTH), migraine, and cluster headaches. This study sought to determine the relationship between puberty and types of headaches. Methods This cross-sectional study was conducted from May 18 to July 31, among female schoolchildren aged between eight and 15 years in the Eastern Province of Saudi Arabia. Respondents were recruited through face-to-face interviews. A self-administered questionnaire was utilized, mainly consisting of demographic data and questions related to diagnosing and managing the impact of puberty in girls on the prevalence of primary headache disorder. Results In total, 481 female schoolchildren were interviewed, mostly between 13 and 15 years old (65.9%). Last year prevalence of headaches was 65.5%, with a significant difference among those who lived in Dhahran (p=0.001) and those with a family history of headaches (p<0.001). The most common type of headache was frequent TTH (16.4%) and chronic TTH (16%). Chronic TTH (p<0.001), frequent TTH (p<0.001), and migraine without aura (p=0.005) were significantly more common among the older age groups.  Conclusion There was a high prevalence of headaches among female schoolchildren, with frequent TTH and chronic TTH being the most common. Furthermore, increasing age was associated with an increasing risk for chronic TTH, frequent TTH, and migraine headaches without aura. More epidemiological studies are necessary to determine the underlying causes of headaches among schoolchildren.

Hybrid Blockchain Platforms for the Internet of Things (IoT): A Systematic Literature Review.

In recent years, research into blockchain technology and the Internet of Things (IoT) has grown rapidly due to an increase in media coverage. Many different blockchain applications and platforms have been developed for different purposes, such as food safety monitoring, cryptocurrency exchange, and secure medical data sharing. However, blockchain platforms cannot store all the generated data. Therefore, they are supported with data warehouses, which in turn is called a hybrid blockchain platform. While several systems have been developed based on this idea, a current state-of-the-art systematic overview on the use of hybrid blockchain platforms is lacking. Therefore, a systematic literature review (SLR) study has been carried out by us to investigate the motivations for adopting them, the domains at which they were used, the adopted technologies that made this integration effective, and, finally, the challenges and possible solutions. This study shows that security, transparency, and efficiency are the top three motivations for adopting these platforms. The energy, agriculture, health, construction, manufacturing, and supply chain domains are the top domains. The most adopted technologies are cloud computing, fog computing, telecommunications, and edge computing. While there are several benefits of using hybrid blockchains, there are also several challenges reported in this study.

Rigid Video Laryngoscopy for Intubation in Severe Pierre Robin Sequence: A Retrospective Review.

OBJECTIVES/HYPOTHESIS: The anatomy of children with severe Pierre Robin sequence can present a challenge for direct laryngoscopy and intubation. Advanced techniques including flexible fiberoptic laryngoscopic intubation have been described but require highly specialized skill and equipment. Rigid video laryngoscopy is more accessible but has not been described in this population. STUDY DESIGN: Retrospective cohort study. METHODS: A retrospective review was completed at a tertiary care center of all children between January 2016 and March 2020 with Pierre Robin sequence who underwent a mandibular distraction osteogenesis procedure. Intubation events were collected, and a descriptive analysis was performed. A univariate logistic regression model was applied to direct laryngoscopy and flexible fiberoptic laryngoscopy with rigid video laryngoscopy as a reference. RESULTS: Twenty-five patients were identified with a total of 56 endotracheal events. All patients were successfully intubated. Direct laryngoscopy was successful at first intubation attempt in 47.3% (9/19) of events. Six direct laryngoscopy events required switching to another device. Rigid video laryngoscopy was successful at first intubation attempt in 80.5% (29/36) of events. Two cases required switching to another device. Flexible fiberoptic laryngoscopy was found successful at first intubation attempt in 88.9% (8/9) of events. Direct laryngoscopy was 4 times more likely to fail first intubation attempt when compared to rigid video laryngoscopy (P < .05). There was no significant difference between rigid video laryngoscopy and flexible fiberoptic laryngoscopy for intubation. CONCLUSIONS: For children with Pierre Robin sequence rigid video laryngoscopy should be considered as a first attempt intubation device both in the operating room and for emergent situations. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1647-1651, 2021.

International Pediatric Otolaryngology Group (IPOG) consensus recommendations: Management of suprastomal collapse in the pediatric population.

INTRODUCTION: Suprastomal Collapse (SuStCo) is a common complication of prolonged tracheostomy in children. There is a paucity of literature on this subject, especially regarding how to manage significant suprastomal collapse that prevents safe decannulation. OBJECTIVE: Provide a definition, classification system, and recommend management options for significant suprastomal collapse in children with tracheostomy. METHODS: Members of the International Pediatric Otolaryngology Group (IPOG) who are experts in pediatric airway conditions were surveyed and results were refined using a modified Delphi method. RESULTS: Consensus was defined as > 70% agreement on a subject. The experts achieved consensus: CONCLUSION: This consensus statement provides recommendations for medical specialists who manage infants and children with tracheostomies with significant Suprastomal Collapse. It provides a classification system to facilitate diagnosis and treatment options for this condition.

Cabozantinib Inhibits Photodynamic Therapy-Induced Auto- and Paracrine MET Signaling in Heterotypic Pancreatic Microtumors.

Extensive desmoplasia is a hallmark of pancreatic ductal adenocarcinoma (PDAC), which frequently associates with treatment resistance. Recent findings indicate that a combination of photodynamic therapy and the multi-kinase inhibitor cabozantinib achieved local tumor control and a significant decrease in tumor metastases in preclinical PDAC models, but the underlying therapeutic mechanisms remain unclear. This study elucidates the molecular basis of this multi-agent regimen, focusing on the role of MET signaling. Since MET activation stems from its interaction with hepatocyte growth factor (HGF), which is typically secreted by fibroblasts, we developed heterotypic PDAC microtumor models that recapitulate these interactions. In these models, MET signaling can be constitutively activated through paracrine and autocrine mechanisms. Photodynamic therapy caused significant elevations in HGF secretion by fibroblasts, suggesting it plays a complex role in the modulation of the paracrine HGF-MET signaling cascade in desmoplastic tumors. Blocking MET phosphorylation with adjuvant cabozantinib caused a significant improvement in photodynamic therapy efficacy, most notably by elevating spheroid necrosis at low radiant exposures. These findings highlight that adjuvant photodynamic therapy can augment chemotherapy efficacies, and potentially achieve improved management of desmoplastic PDAC in a more tolerable manner.

Reversible external auditory canal ligation (REACL): A novel surgical technique to induce transient and reversible hearing loss in developing rats.

BACKGROUND: Cases of sensory loss provide an excellent model to study the plastic nature of cortical sensory systems. Models of reversible sensory loss are particularly useful for establishing the timeline of various critical periods for cortical plasticity. However, there currently is an absence of adequate methods to produce reversible hearing loss in neonatal and developing rodents. NEW METHOD: We propose a novel and reversible adaptation of an existing surgical technique-external auditory canal ligation (EACL)-that produces a reliable and moderate hearing loss. RESULTS: Auditory brainstem responses (ABRs) were used to measure both the magnitude of the hearing loss induced by EACL and the auditory thresholds following hearing restoration. The EACL and reopening procedures, as assessed by visual inspection, had success rates of 81% and 78%, respectively. The average hearing thresholds, as assessed with ABRs, increased by nearly 40 decibels across all tested frequencies. Hearing thresholds returned to normal levels following the reopening procedure. COMPARISON WITH EXISTING METHODS: Our procedure yields similar benefits to other methods, such as producing a reliable and moderate hearing loss that is entirely reversible. Furthermore, to our knowledge, it is the first that can be performed in neonatal rodents, thus allowing researchers the opportunity to assess the effects of sensory loss on behavior and cortical neurophysiology during developmental critical periods. CONCLUSION: Our modified technique of reversible external auditory canal ligation offers an easy, and reliable method to induce a transient state of hearing loss that mimics naturally occurring congenital conductive hearing loss.

Outpatient management of pediatric acute mastoiditis.

OBJECTIVE: Evaluate the Montreal Children's Hospital experience with outpatient management of uncomplicated acute mastoiditis with parenteral antibiotic therapy alone and determine if it is a safe alternative to inpatient management. SUBJECTS AND METHOD: A retrospective review of pediatric patients diagnosed with acute mastoiditis at a tertiary care pediatric hospital between 2013 and 2015 was performed. Patients with syndromes, immunodeficiency, cholesteatoma, chronic otitis media, cochlear implant in the affected ear, or incidental mastoid opacity were excluded. RESULTS: 56 children age 6 months to 15 years old were treated for acute mastoiditis, including 29 hospitalizations and 27 outpatients. Patients managed as outpatient with daily intravenous ceftriaxone had a 93% cure rate. Eighteen hospitalized and one outpatient had complications of acute mastoiditis. Children with complications were more likely to be febrile (p = 0.045). Two patients failed outpatient therapy and were admitted; one for myringotomy and piperacillin-tazobactam treatment and one required a mastoidectomy. 4/27 children treated as outpatient underwent myringotomy and tube insertion, 2 underwent myringotomy and tube along with admission and 21 did not require tube insertion. The average total duration of intravenous antibiotic therapy was respectively 4.9 and 18.9 days in the outpatient and hospitalized group. The average duration of admission was 5.9 days. CONCLUSION: Outpatient medical therapy of uncomplicated pediatric mastoiditis is safe, successful, and efficient. Benefits include efficient use of surgical beds, cost savings and patient and family convenience. Careful patient selection and close monitoring are keys for successful outcome.

Characterization of a novel adult murine immortalized microglial cell line and its activation by amyloid-beta.

BACKGROUND: Alzheimer's disease is associated with amyloid-beta (Aß)-induced microglia activation. This pro-inflammatory response promotes neuronal damage, and therapies are sought to limit microglial activation. Screening efforts to develop new pharmacological inhibitors require a robust in vitro cell system. Current models lack significant responses to Aß, and their use in examining age-related neurodegenerative diseases is questionable. For example, the commonly used BV-2 microglial line was derived from embryonic mononuclear cells and its activation by various stimuli is limited. To this end, we have established a new immortalized microglial (IMG) cell line from adult murine brain. The objective of this study was to characterize Aß-induced activation of IMG cells, and here, we demonstrate the ability of cannabinoids to significantly reduce this inflammatory response. METHODS: Microglial cells derived from adult murine brain were immortalized via infection with the v-raf/v-myc retrovirus under conditions that selectively promote microglia growth. The presence or absence of markers CD11b and F4/80 (microglial), NeuN (neuronal), and GFAP (astrocytic) was assessed by immunofluorescence microscopy and western blotting. Using IMG and BV-2 cells, levels of pro- and anti-inflammatory transcripts in response to extracellular stimuli were determined by quantitative PCR (qPCR). Phagocytosis of fluorescent beads and fluorescein isothiocyanate (FITC)-labeled Aß oligomers was assessed using flow cytometry and fluorescence microscopy. FITC-Aß uptake was quantified using a fluorescence plate reader. The ability of cannabinoids to mitigate Aß-induced expression of inducible nitric oxide synthase (iNOS) was evaluated. RESULTS: IMG cells express the microglial markers CD11b and F4/80 but not NeuN or GFAP. Relative to BV-2 cells, IMG cells increased iNOS (>200-fold) and Arg-1 (>100-fold) in response to pro- and anti-inflammatory stimuli. IMG cells phagocytose foreign particles and Aß oligomers, with the latter trafficked to phagolysosomes. Aß-induced activation of IMG cells was suppressed by delta-9-tetrahydrocannabinol and the CB2-selective agonist JWH-015 in a time- and concentration-dependent manner. CONCLUSIONS: IMG cells recapitulate key features of microglial cell activation. As an example of their potential pharmacological use, cannabinoids were shown to reduce activation of Aß-induced iNOS gene expression. IMG cells hold promising potential for drug screening, mechanistic studies, and functional investigations directed towards understanding how Aß interacts with microglia.

The small molecule ferristatin II induces hepatic hepcidin expression in vivo and in vitro.

Previous studies have shown that administration of ferristatin II to rats is associated with decreased serum iron, reduced transferrin saturation, and increased hepatic hepcidin expression. BMP and IL-6 signaling act via Smad and Stat3 transcription factors, respectively, to increase expression of hepcidin, the master regulator of iron metabolism. In this study, we aimed to explore the underlying mechanism of ferristatin II action on hepcidin production. We found that ferristatin II greatly increased hepcidin expression both in vivo and in vitro. In the rat liver, ferristatin II treatment decreased expression of Smad downstream targets Smad7 and Id1 and increased expression of Stat3 downstream targets α-2-macroglobulin, α-1-acid glycoprotein, and C-reactive peptide. Ferristatin II also increased Stat3 phosphorylation in the rat liver without affecting serum or hepatic IL-6 levels. It is unclear whether the Stat3 activation observed in vivo is a cause or a consequence to hepcidin induction. Reporter gene expression studies demonstrated that ferristatin II synergized with BMP6 and IL-6 to enhance hepcidin expression in vitro. However, this synergy was not due to activation of either Smad or Stat3 signaling, raising the possibility that ferristatin II may activate a novel pathway for hepcidin regulation.

The significance of ferritin in cancer: anti-oxidation, inflammation and tumorigenesis.

The iron storage protein ferritin has been continuously studied for over 70years and its function as the primary iron storage protein in cells is well established. Although the intracellular functions of ferritin are for the most part well-characterized, the significance of serum (extracellular) ferritin in human biology is poorly understood. Recently, several lines of evidence have demonstrated that ferritin is a multi-functional protein with possible roles in proliferation, angiogenesis, immunosuppression, and iron delivery. In the context of cancer, ferritin is detected at higher levels in the sera of many cancer patients, and the higher levels correlate with aggressive disease and poor clinical outcome. Furthermore, ferritin is highly expressed in tumor-associated macrophages which have been recently recognized as having critical roles in tumor progression and therapy resistance. These characteristics suggest ferritin could be an attractive target for cancer therapy because its down-regulation could disrupt the supportive tumor microenvironment, kill cancer cells, and increase sensitivity to chemotherapy. In this review, we provide an overview of the current knowledge on the function and regulation of ferritin. Moreover, we examine the literature on ferritin's contributions to tumor progression and therapy resistance, in addition to its therapeutic potential.

Ferritin stimulates breast cancer cells through an iron-independent mechanism and is localized within tumor-associated macrophages.

Tumor-associated macrophages play a critical role in breast tumor progression; however, it is still unclear what effector molecular mechanisms they employ to impact tumorigenesis. Ferritin is the primary intracellular iron storage protein and is also abundant in circulation. In breast cancer patients, ferritin is detected at higher levels in both serum and tumor lysates, and its increase correlates with poor clinical outcome. In this study, we comprehensively examined the distribution of ferritin in normal and malignant breast tissue at different stages in tumor development. Decreased ferritin expression in cancer cells but increased infiltration of ferritin-rich CD68-positive macrophages was observed with increased tumor histological grade. Interestingly, ferritin stained within the stroma surrounding tumors suggesting local release within the breast. In cell culture, macrophages, but not breast cancer cells, were capable of ferritin secretion, and this secretion was further increased in response to pro-inflammatory cytokines. We next examined the possible functional significance of extracellular ferritin in a breast cancer cell culture model. Ferritin stimulated the proliferation of the epithelial breast cancer cell lines MCF7 and T47D. Moreover, this proliferative effect was independent of the iron content of ferritin and did not increase intracellular iron levels in cancer cells indicating a novel iron-independent function for this protein. Together, these findings suggest that the release of ferritin by infiltrating macrophages in breast tumors may represent an inflammatory effector mechanism by which ferritin directly stimulates tumorigenesis.

Elevation in inflammatory serum biomarkers predicts response to trastuzumab-containing therapy.

Approximately half of all HER2/neu-overexpressing breast cancer patients do not respond to trastuzumab-containing therapy. Therefore, there remains an urgent and unmet clinical need for the development of predictive biomarkers for trastuzumab response. Recently, several lines of evidence have demonstrated that the inflammatory tumor microenvironment is a major contributor to therapy resistance in breast cancer. In order to explore the predictive value of inflammation in breast cancer patients, we measured the inflammatory biomarkers serum ferritin and C-reactive protein (CRP) in 66 patients immediately before undergoing trastuzumab-containing therapy and evaluated their progression-free and overall survival. The elevation in pre-treatment serum ferritin (>250 ng/ml) or CRP (>7.25 mg/l) was a significant predictor of reduced progression-free survival and shorter overall survival. When patients were stratified based on their serum ferritin and CRP levels, patients with elevation in both inflammatory biomarkers had a markedly poorer response to trastuzumab-containing therapy. Therefore, the elevation in inflammatory serum biomarkers may reflect a pathological state that decreases the clinical efficacy of this therapy. Anti-inflammatory drugs and life-style changes to decrease inflammation in cancer patients should be explored as possible strategies to sensitize patients to anti-cancer therapeutics.

Nuclear ferritin: A new role for ferritin in cell biology.

BACKGROUND: Ferritin has been traditionally considered a cytoplasmic iron storage protein. However, several studies over the last two decades have reported the nuclear localization of ferritin, specifically H-ferritin, in developing neurons, hepatocytes, corneal epithelial cells, and some cancer cells. These observations encouraged a new perspective on ferritin beyond iron storage, such as a role in the regulation of iron accessibility to nuclear components, DNA protection from iron-induced oxidative damage, and transcriptional regulation. SCOPE OF REVIEW: This review will address the translocation and functional significance of nuclear ferritin in the context of human development and disease. MAJOR CONCLUSIONS: The nuclear translocation of ferritin is a selective energy-dependent process that does not seem to require a consensus nuclear localization signal. It is still unclear what regulates the nuclear import/export of ferritin. Some reports have implicated the phosphorylation and O-glycosylation of the ferritin protein in nuclear transport; others suggested the existence of a specific nuclear chaperone for ferritin. The data argue strongly for nuclear ferritin as a factor in human development and disease. Ferritin can bind and protect DNA from oxidative damage. It also has the potential of playing a regulatory role in transcription. GENERAL SIGNIFICANCE: Nuclear ferritin represents a novel new outlook on ferritin functionality beyond its classical role as an iron storage molecule.