Inflammatory Bowel Disease: A Comprehensive Analysis of Molecular Bases, Predictive Biomarkers, Diagnostic Methods, and Therapeutic Options.

In inflammatory bowel diseases (IBDs), such as Crohn's disease (CD) and ulcerative colitis (UC), the immune system relentlessly attacks intestinal cells, causing recurrent tissue damage over the lifetime of patients. The etiology of IBD is complex and multifactorial, involving environmental, microbiota, genetic, and immunological factors that alter the molecular basis of the organism. Among these, the microbiota and immune cells play pivotal roles; the microbiota generates antigens recognized by immune cells and antibodies, while autoantibodies target and attack the intestinal membrane, exacerbating inflammation and tissue damage. Given the altered molecular framework, the analysis of multiple molecular biomarkers in patients proves exceedingly valuable for diagnosing and prognosing IBD, including markers like C reactive protein and fecal calprotectin. Upon detection and classification of patients, specific treatments are administered, ranging from conventional drugs to new biological therapies, such as antibodies to neutralize inflammatory molecules like tumor necrosis factor (TNF) and integrin. This review delves into the molecular basis and targets, biomarkers, treatment options, monitoring techniques, and, ultimately, current challenges in IBD management.

Lipid fingerprint-based histology accurately classifies nevus, primary melanoma, and metastatic melanoma samples.

Probably, the most important factor for the survival of a melanoma patient is early detection and precise diagnosis. Although in most cases these tasks are readily carried out by pathologists and dermatologists, there are still difficult cases in which no consensus among experts is achieved. To deal with such cases, new methodologies are required. Following this motivation, we explore here the use of lipid imaging mass spectrometry as a complementary tool for the aid in the diagnosis. Thus, 53 samples (15 nevus, 24 primary melanomas, and 14 metastasis) were explored with the aid of a mass spectrometer, using negative polarity. The rich lipid fingerprint obtained from the samples allowed us to set up an artificial intelligence-based classification model that achieved 100% of specificity and precision both in training and validation data sets. A deeper analysis of the image data shows that the technique reports important information on the tumor microenvironment that may give invaluable insights in the prognosis of the lesion, with the correct interpretation.

Pediatric Spontaneous Cerebrospinal Fluid Leak Repair: An Endoscopic Endonasal Approach.

Background: Spontaneous cerebrospinal fluid (CSF) rhinorrhea in the pediatric population is an exceedingly rare condition that occurs when the dura mater is breached, resulting in CSF drainage from the subarachnoid space into surrounding sinonasal tissue. Objective: This work delineates a step-by-step surgical approach to visually demonstrate the feasibility of an uninarial endoscopic endonasal approach for pediatric spontaneous CSF leak repair. Postoperative Outcome: A 2-year-old male with a 6-month history of clear rhinorrhea, intermittent headaches, and a previous episode of bacterial meningitis was evaluated as an inpatient consultation. Computed tomography cisternography revealed active CSF extravasation at the right sphenoid sinus roof. An endoscopic endonasal approach was performed including a complete sphenoethmoidectomy plus middle turbinectomy to provide access to the skull base defect. Once identified, a middle turbinate free mucosal graft was placed for cranial base reconstruction given the child's young agre. Sinonasal debridement 3 weeks following surgery under anesthesia revealed an intact viable graft with no evidence of CSF leak. There was no evidence of CSF leak recurrence or complications 1 year following surgery. Conclusion: The uninarial endoscopic endonasal approach is a safe and effective option for the surgical management of spontaneous CSF leak rhinorrhea in the pediatric population.

Deer mastadenovirus B pneumonia in a white-tailed deer fawn.

A 7-mo-old farmed white-tailed deer fawn (Odocoileus virginianus) died after several weeks of progressive deterioration associated with endoparasitism and respiratory signs. A field autopsy was performed, and lung tissue was submitted for histologic examination. The findings were consistent with necrosuppurative bronchointerstitial pneumonia with intranuclear viral inclusions. Immunofluorescence using fluorescently labeled polyclonal antibodies to bovine adenovirus 3 and 5 was positive. To rule out cross-reactivity with other adenoviruses, formalin-fixed, paraffin-embedded tissue sections were submitted for genome sequence analysis, which revealed a 99.6% match to Deer mastadenovirus B (formerly Odocoileus adenovirus 2, OdAdV2). To our knowledge, natural clinical disease associated with OdAdV2 has not been reported previously.

Endoscopic-Indocyanine Green Angiography Assisted Microtia Reconstruction.

Described herein is an innovative, minimally-invasive technique to harvest temporoparietal fascia flap used in implant-based ear reconstruction for children with microtia. This technique utilizes a never previously described application of intra-operative Indocyanine Green Angiography to optimize flap viability and minimizing the risk of facial nerve injury. Laryngoscope, 133:3615-3618, 2023.

Dual Option Microtia Clinic: A Comparison of Outcomes in Microtia Reconstruction Using Autologous Rib or Porous Polyethylene Implant.

Introduction: Auricular reconstruction techniques most frequently utilize either autologous costal cartilage or alloplastic porous polyethylene (PPE) implant. Objectives: To compare the aesthetic outcomes, number of surgeries, and complications in children who underwent microtia reconstruction with either rib or PPE implant by blinded photograph review. Methods: This retrospective cohort study included consecutive pediatric patients who underwent auricular reconstruction with either autologous cartilage or PPE between November 2017 and February 2022. Blinded observers rated each postoperative ear through a web-based survey. Data on patient characteristics, operative time, length of admission, and complications were collected, bivariate analyses were performed using chi-square or Fisher's exact tests for categorical variables and Wilcoxon rank-sum test for continuous variables. Results: Forty-four ears were included, 28 of which (63.6%) were reconstructed with cartilage. Median patient age was 8 years (range 4-18 years) and 29 (65.9%) were male. The cartilage group had more surgeries (median 2.5 vs. 1.0, p < 0.001), and total operating time across all surgeries did not differ significantly. Conclusion: The two groups in our study had similar rates of complications and aesthetic scores, and aesthetic scores were worse for ears with wound complications requiring unplanned revisions.

Management of Recurrent Fibromatosis Colli with Innervated Vastus Lateralis Free Flap.

Fibromatosis colli (FC) is a fibroblastic contracture of the sternocleidomastoid muscle, often presenting as a neck mass and torticollis. The vast majority of cases resolve with conservative measures; for persistent disease, surgical tenotomy is offered. This is a case of a 4-year-old patient with large FC who failed conservative treatment as well as surgical release and ultimately underwent complete excision and reconstruction with innervated vastus lateralis free flap. We describe a novel application of this free flap for a difficult clinical scenario. Laryngoscope, 133:2025-2028, 2023.

Characterization of the Antitumor Potential of Extracts of Cannabis sativa Strains with High CBD Content in Human Neuroblastoma.

Cannabis has been used for decades as a palliative therapy in the treatment of cancer. This is because of its beneficial effects on the pain and nausea that patients can experience as a result of chemo/radiotherapy. Tetrahydrocannabinol and cannabidiol are the main compounds present in Cannabis sativa, and both exert their actions through a receptor-mediated mechanism and through a non-receptor-mediated mechanism, which modulates the formation of reactive oxygen species. These oxidative stress conditions might trigger lipidic changes, which would compromise cell membrane stability and viability. In this sense, numerous pieces of evidence describe a potential antitumor effect of cannabinoid compounds in different types of cancer, although controversial results limit their implementation. In order to further investigate the possible mechanism involved in the antitumoral effects of cannabinoids, three extracts isolated from Cannabis sativa strains with high cannabidiol content were analyzed. Cell mortality, cytochrome c oxidase activity and the lipid composition of SH-SY5Y cells were determined in the absence and presence of specific cannabinoid ligands, with and without antioxidant pre-treatment. The cell mortality induced by the extracts in this study appeared to be related to the inhibition of the cytochrome c oxidase activity and to the THC concentration. This effect on cell viability was similar to that observed with the cannabinoid agonist WIN55,212-2. The effect was partially blocked by the selective CB1 antagonist AM281, and the antioxidant α-tocopherol. Moreover, certain membrane lipids were affected by the extracts, which demonstrated the importance of oxidative stress in the potential antitumoral effects of cannabinoids.

Dot Immunobinding Assay for the Rapid Serodetection of Scedosporium/Lomentospora in Cystic Fibrosis Patients.

The detection of Scedosporium/Lomentospora is still based on non-standardized low-sensitivity culture procedures. This fact is particularly worrying in patients with cystic fibrosis (CF), where these fungi are the second most common filamentous fungi isolated, because a poor and delayed diagnosis can worsen the prognosis of the disease. To contribute to the discovery of new diagnostic strategies, a rapid serological dot immunobinding assay (DIA) that allows the detection of serum IgG against Scedosporium/Lomentospora in less than 15 min was developed. A crude protein extract from the conidia and hyphae of Scedosporium boydii was employed as a fungal antigen. The DIA was evaluated using 303 CF serum samples (162 patients) grouped according to the detection of Scedosporium/Lomentospora in the respiratory sample by culture, obtaining a sensitivity and specificity of 90.48% and 79.30%, respectively; positive and negative predictive values of 54.81% and 96.77%, and an efficiency of 81.72%. The clinical factors associated with the results were also studied using a univariate and a multivariate analysis, which showed that Scedosporium/Lomentospora positive sputum, elevated anti-Aspergillus serum IgG and chronic Pseudomonas aeruginosa infection were significantly associated with a positive result in DIA, while Staphylococcus aureus positive sputum showed a negative association. In conclusion, the test developed can offer a complementary, rapid, simple and sensitive method to contribute to the diagnosis of Scedosporium/Lomentospora in patients with CF.

Pediatric Invasive Fungal Rhinosinusitis: A Comprehensive Analysis of Prognostic Factors for Survival.

OBJECTIVE: Pediatric invasive fungal rhinosinusitis (IFS) is a devastating infection that manifests almost exclusively in immunocompromised children. The goal of this work was to determine which clinical features carry prognostic value for survival. METHODS: A retrospective review of children with a histopathological diagnosis of IFS was performed at an academic tertiary care institution from 1990 to 2021. Clinical variables were collected to generate survival and life-table estimators at 6-months and 1-year. RESULTS: Eighteen patients were included in this analysis, with a mean age of 9.8 years (range, 1-17 years). Most children were neutropenic (n = 15, 83.3%), with acute lymphoblastic leukemia (n = 10, 55.6%) representing the most common primary diagnosis. A mean of 3.2 operations (range 1-7 operations) was performed per patient for either mucormycosis (n = 10, 55.6%) or aspergillosis (n = 8, 44.4%). The mean time to absolute neutrophil count recovery was 65.8 days (range 20-137 days), with a 6-month and 1-year survival rate of 47.6% and 41.7%, respectively. Gross total resection (p = 0.006, p < 0.001), number of antifungals (p = 0.0004, p = 0.0003), and total operation number (p = 0.0032, p = 0.0035), served as positive prognostic factors for 6-month and 1-year survival. Conversely, altered mental status (p = 0.0026), cerebral involvement (p = 0.0010), cranial neuropathies (p < 0.0001), hyperglycemia (p = 0.0445, p = 0.0208), and intensive care unit status (p = 0.0013) served as negative prognostic factors for 6-month and 1-year survival. CONCLUSION: Several key elements were identified and found to play a vital role in influencing survival for pediatric IFS. Early diagnosis, prompt medical therapy, and aggressive surgical intervention remain at the forefront in the treatment of this complex opportunistic infection. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1239-1250, 2023.

Outcomes after combined excisional goniotomy and manual small incision cataract surgery.

AIM: To report the long-term outcomes of combined excisional goniotomy and manual small incision cataract surgery (MSICS). METHODS: This is a retrospective case series of patients with open angle glaucoma and visually significant cataracts that underwent combined excisional goniotomy and MSICS with one-year follow-up. The medical history, demographic information, and clinical characteristics of each case were recorded. Data regarding changes in vision, intraocular pressure (IOP), the number of glaucoma medications, and the evolution of the disease after surgery were reported. RESULTS: Three patients, with open angle glaucoma and cataracts underwent combined excisional goniotomy and MSICS without adverse events. All patients had improvement in vision compared to baseline measurements. The range of IOP at baseline was from 14 to 18 mm Hg and decrease to a range of 10 to 14 mm Hg after one year of follow-up. Additionally, two patients also decreased their dependence on IOP-lowering medications at the last follow up visit with one patient maintaining baseline level of medication use. CONCLUSION: A combination of excisional goniotomy and MSICS illustrates both the safety and efficacy to treat patients with visually significant cataract and glaucoma. This procedure allows for a more cost-effective surgical approach that matches the needs of resource strained territories around the globe.

Malignancy Rates by Bethesda Subcategory in the Pediatric Population.

INTRODUCTION: While the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is the most widely used method for categorizing thyroid nodules, its applicability to children is often debated. We describe our institution's experience utilizing the TBSRTC and examine the rates of malignancy in our population. METHODS: We conducted a retrospective chart review of eligible patients undergoing primary thyroidectomy at a high-volume tertiary care pediatric hospital. All patients had pre-operative fine needle aspiration. RESULTS: Of the 112 patients in our cohort, 85 (76%) were female. The median age was 15.1 years. The patients were divided into groups based on the Bethesda categorization of the fine needle aspirations of their nodules. The percentages of patients whose resection specimens showed evidence of malignancy on the surgical pathology reports were recorded as follows: category I (n = 5): 20%, category II (n = 11): 0%, category III (n = 30): 17%, category IV (n = 13): 31%, category V (n = 17): 94% and category VI (n = 36): 100%. CONCLUSION: Our findings indicate that the malignancy rates at our institution are comparable to those reported by other high-volume studies. When compared with the 2017 TBSRTC data, we found that our results were similar in many categories, with the exception of categories I and V.

Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors.

Lung cancer is frequently caused by activating mutations in the epidermal growth factor receptor (EGFR). Allosteric EGFR inhibitors offer promise as the next generation of therapeutics, as they are unaffected by common ATP-site resistance mutations and synergize with the drug osimertinib. Here, we examine combinations of ATP-competitive and allosteric inhibitors to better understand the molecular basis for synergy. We identify a subset of irreversible EGFR inhibitors that display positive binding cooperativity and synergy with the allosteric inhibitor JBJ-04-125-02 in several EGFR variants. Structural analysis of these complexes reveals conformational changes occur mainly in the phosphate-binding loop (P-loop). Mutation of F723 in the P-loop reduces cooperative binding and synergy, supporting a mechanism in which F723-mediated contacts between the P-loop and the allosteric inhibitor are critical for synergy. These structural and mechanistic insights will aid in the identification and development of additional inhibitor combinations with potential clinical value.

Incidence of thymic tissue in pediatric thyroidectomy.

OBJECTIVES: The nuances in the technical approach to pediatric thyroidectomy have been sparsely reported in the literature. No previous studies have reported on the rates of unintentional thymic tissue excision during pediatric thyroidectomy. In this study, we sought to describe the rates of thymic tissue excision noted on surgical specimens from pediatric thyroidectomies and investigate any correlations with preoperative factors and long-term outcomes. METHODS: A retrospective chart review was conducted of patients who underwent thyroidectomy at a tertiary care children's hospital between January 2010 and October 2020. Presence of thymic tissue (PTT) was defined as any pathologist-documented evidence of thymic tissue in the surgical specimen. Patient characteristics, operative details, and disease related datapoints were investigated for any correlation with PTT. RESULTS: Of the 209 patients who underwent thyroidectomy in the study period, 53 (25%) had PTT. After conducting a stepwise multivariate analysis, those with a concomitant central neck dissection had 3.3 times the odds of having PTT as compared to those with no neck dissection (p = 0.013, 95%CI: 1.3, 8.3). Additionally, patients with evidence of incidental parathyroidectomy had 8.99 times the odds of also having PTT as compared to those without IPE (p < 0.001, 95%CI: 4.0, 20.1). CONCLUSION: This is the first report analyzing the rate of thymic tissue excision during pediatric thyroidectomy. Thyroid surgeons should be prepared to encounter thymic tissue during pediatric cases and be aware of its associated risk of incidental parathyroid gland excision and dissection of tissue beyond intended surgical limits.

Interim Analysis of STREAMLINE® Surgical System Clinical Outcomes in Eyes with Glaucoma.

Purpose: To characterize the clinical outcomes of a novel ab interno minimally invasive procedure with the STREAMLINE® Surgical System for creation of incisional goniotomies and canal of Schlemm viscodilation in eyes with mild to severe primary open-angle glaucoma (POAG). Methods: In a prospective, single-arm, first-in-human case series, 20 eyes of 20 subjects with mild to severe POAG underwent creation of incisional goniotomies and canal of Schlemm viscodilation following phacoemulsification cataract extraction after washout of all intraocular pressure (IOP)-lowering medications. The angle surgery portion was performed with a single-use handpiece tipped with a microcannula that creates precise goniotomies through the trabecular meshwork into the canal of Schlemm and delivers a small volume of ophthalmic viscosurgical device directly into the canal via precise catheterization. Outcomes in this interim analysis included mean reduction in IOP and medications through 6 months of follow-up, as well as the proportion of eyes achieving IOP reduction ≥20% from baseline. Results: At month 6, mean IOP reduction of ≥20% from baseline was achieved in 89.5% of eyes (17/19). Mean (standard deviation) medicated IOP at screening was 16.3 (3.6) mmHg and unmedicated baseline IOP (after washout) was 23.5 (2.5) mmHg. Mean IOP was significantly reduced from baseline through 6 months of follow-up to 14.7 (2.4) mmHg (p<0.001), representing an IOP reduction of 8.8 mmHg (36.9%). Overall, 57.9% (11/19) of eyes decreased dependence on IOP-lowering medications by at least one medication, and 42.1% (8/19) were medication free. Mean medication use was reduced from 2.0 (0.8) at screening to 1.1 (1.1) at 6 months (p<0.001). Three eyes had transient IOP spikes treated with topical medications. Conclusion: The creation of incisional goniotomies and canal of Schlemm viscodilation safely and effectively reduced IOP and the need for IOP-lowering medications by both clinically and statistically significant magnitudes in eyes with mild to severe POAG undergoing concomitant phacoemulsification cataract extraction through the first 6 months of follow-up.

PICU admission and complications following adenotonsillectomies in pediatric patients: A retrospective cohort study.

BACKGROUND: Children with obstructive sleep apnea (OSA) have higher risks of post-operative respiratory complication after adenotonsillectomy. However, there is no clinical standard criteria for pediatric intensive care unit (PICU) admission following adenotonsillectomy. The purpose of this study was to identify perioperative risk factors associated with the need for PICU level care after adenotonsillectomy. METHODS: We performed a retrospective chart review of children with severe OSA (apnea hypopnea index on polysomnography; AHI ≥10) and/or post-operative PICU admission at a tertiary academic center from May 2010 to September 2018. We collected demographics, pre-existing comorbidities, perioperative medications, and post-operative complications. We defined a primary outcome as escalation of airway management while in the PICU or PICU stay >48 h. Airway escalation included the need for an invasive airway, new CPAP application, increased CPAP setting, or increased supplemental oxygen. RESULTS: Analysis included 278 children with severe OSA and/or PICU admission. Median age was 6.6 years old; 181 (65%) were admitted to the PICU, and 60 (21.5%) had the composite outcome of escalation of airway management or prolonged stay. In patients with an escalation of airway management, 28 needed intubation or mechanical ventilation. Multivariable logistic regression showed intraoperative respiratory complications, polysomnography (PSG) peak end-tidal CO2 (EtCO2) reading >60 mmHg, and the presence of neuromuscular disease as significant associated factors for escalation of airway management or prolonged PICU stay (P values < 0.01; odd ratios 3.4, 5.3, and 5.4, respectively). CONCLUSION: For children following adenotonsillectomy, PSG EtCO2 ≥ 60%, preexisting neuromuscular disease, and intraoperative complications (hypoxia, difficult airway, etc.) were independently associated with escalation of airway management or prolonged stay. AHI was not an independent predictor for PICU complication. We concluded factors should be considered for PICU admission in addition to AHI.

Upregulated phospholipase D2 expression and activity is related to the metastatic properties of melanoma.

The incidence rates of melanoma have increased steadily in recent decades and nearly 25% of the patients diagnosed with early-stage melanoma will eventually develop metastasis, for which there is currently no fully effective treatment. The link between phospholipases and tumors has been studied extensively, particularly in breast and colon cancers. With the aim of finding new biomarkers and therapeutic options for melanoma, the expression of different phospholipases was assessed in 17 distinct cell lines in the present study, demonstrating that phospholipase D2 (PLD2) is upregulated in metastatic melanoma as compared to normal skin melanocytes. These results were corroborated by immunofluorescence and lipase activity assays. Upregulation of PLD2 expression and increased lipase activity were observed in metastatic melanoma relative to normal skin melanocytes. So far, the implication of PLD2 activity in melanoma malignancies has remained elusive. To the best of our knowledge, the present study was the first to demonstrate that the overexpression of PLD2 enhances lipase activity, and its effect to increase the proliferation, migration and invasion capacity of melanoma cells was assessed with XTT and Transwell assays. In addition, silencing of PLD2 in melanoma cells reduced the metastatic potential of these cells. The present study provided evidence that PLD2 is involved in melanoma malignancy and in particular, in its metastatic potential, and established a basis for future studies evaluating PLD2 blockade as a therapeutic strategy to manage this condition.

Thyroid tumor ratio: Improving the assessment of the impact of size in pediatric thyroid cancer.

BACKGROUND: The impact of thyroid nodule size is less useful in children who have smaller thyroid volumes than in adults. We investigate using a novel thyroid tumor ratio measurement in children with thyroid cancer. METHODS: Patient and pathologic characteristics were investigated via Student's t-test in a univariate analysis for any correlation with the log-transformed tumor ratio, followed by a multivariate linear regression. RESULTS: Of 75 patients with malignancy and tumor ratio information, mean ratio decreased with increasing age (p = 0.04). Out of several clinical factors, patients with lymph node metastases and those treated with postoperative radioactive iodine had significantly higher mean tumor ratios on multivariate analysis (p = 0.04 for both factors). CONCLUSIONS: Our study is the first to describe thyroid tumor volume in pediatric thyroid cancer and shows that increased tumor ratio was associated with indicators of more advanced disease such as lymph node metastases and use of radioactive iodine.

Investigation of SARS-CoV-2 infection and associated lesions in exotic and companion animals.

Documented natural infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in exotic and companion animals following human exposures are uncommon. Those documented in animals are typically mild and self-limiting, and infected animals have only infrequently died or been euthanized. Through a coordinated One Health initiative, necropsies were conducted on 5 animals from different premises that were exposed to humans with laboratory-confirmed SARS-CoV-2 infection. The combination of epidemiologic evidence of exposure and confirmatory real-time reverse transcriptase-polymerase chain reaction testing confirmed infection in 3 cats and a tiger. A dog was a suspect case based on epidemiologic evidence of exposure but tested negative for SARS-CoV-2. Four animals had respiratory clinical signs that developed 2 to 12 days after exposure. The dog had bronchointerstitial pneumonia and the tiger had bronchopneumonia; both had syncytial-like cells with no detection of SARS-CoV-2. Individual findings in the 3 cats included metastatic mammary carcinoma, congenital renal disease, and myocardial disease. Based on the necropsy findings and a standardized algorithm, SARS-CoV-2 infection was not considered the cause of death in any of the cases. Continued surveillance and necropsy examination of animals with fatal outcomes will further our understanding of natural SARS-CoV-2 infection in animals and the potential role of the virus in development of lesions.