Pan AMPK Activation Protects Tubules in Rat Ischemic Acute Kidney Injury.

Acute Kidney Injury (AKI) is characterized by an abrupt decline in kidney function and has been associated with excess risks of death, kidney disease progression, and cardiovascular events. The kidney has a high energetic demand with mitochondrial health being essential to renal function and damaged mitochondria has been reported across AKI subtypes. 5' adenosine monophosphate-activated protein kinase (AMPK) activation preserves cellular energetics through improvement of mitochondrial function and biogenesis when ATP levels are low such as under ischemia-induced AKI. We developed a selective potent small molecule pan AMPK activator, compound 1, and tested its ability to increase AMPK activity and preserve kidney function during ischemia/reperfusion injury in rats. A single administration of 1 caused sustained activation of AMPK for at least 24 hours, protected against acute tubular necrosis, and reduced clinical markers of tubular injury such as NephroCheck and Fractional Excretion of Sodium (FENa). Reduction in plasma creatinine and increased Glomerular Filtration Rate (GFR) indicated preservation of kidney function. Surprisingly, we observed a strong diuretic effect of AMPK activation associated with natriuresis both with and without AKI. Our findings demonstrate that activation of AMPK leads to protection of tubular function under hypoxic/ischemic conditions which holds promise as a potential novel therapeutic approach for AKI. Significance Statement No approved pharmacological therapies currently exist for acute kidney injury. We developed Compound 1 which dose-dependently activated AMPK in the kidney and protected kidney function and tubules after ischemic renal injury in the rat. This was accompanied by natriuresis in injured as well as uninjured rats.

Recalcitrant Stenosis Following Pediatric LTR: Contributing Factors and Clinical Impact.

OBJECTIVES: Laryngotracheal reconstruction (LTR) has revolutionized the management of pediatric subglottic stenosis (SGS). However, postoperative stenosis remains a difficult hurdle to overcome. Our goal is to determine the clinical impact of recalcitrant stenosis after LTR and the factors contributing to postoperative stenosis. STUDY DESIGN: Retrospective review of 181 open LTR patients between 2008 and 2021. SETTING: Stand-alone tertiary children's hospital. METHODS: Recalcitrant stenosis was defined as new or worsening stenosis despite open LTR. Fisher's exact and Mann-Whitney tests were used to detect differences in categorical and continuous clinical data between patients with and without treatment-resistant stenosis. Time-to-decannulation analysis of both groups was performed using Kaplan-Meier analysis and evaluated with log-rank and Cox proportional hazards regression. Multivariate logistical regression was used to assess the validity of associations found in univariate analysis. RESULTS: As expected, the 27 patients with postoperative stenosis were less likely to be decannulated (P < .001, Fisher's Exact), more likely to require a postoperative tracheostomy (P < .001, Fisher's Exact) or revision LTR (P < .001, Fisher's Exact) and had prolonged time to decannulation (P < .001, Log-rank). Children with Grade IV SGS (P = .004, Fisher's Exact), and those with longer suprastomal stent duration (P = .03, Fisher's Exact) were more likely to suffer from recalcitrant stenosis. Stent duration longer than 4 weeks (P = .01) contributed to refractory stenosis when controlling for all aforementioned variables using multivariable logistic regression. Interposition grafts had a protective effect (P = .005). CONCLUSION: Maintaining suprastomal stents over 4 weeks after LTR increases the risk for postoperative stenosis and its sequelae.

Risk of post-tonsillectomy hemorrhage among COVID-19 positive pediatric patients.

OBJECTIVE: COVID-19 infection has been demonstrated to increase risk for post-operative bleeding. This study investigated the impact of COVID-19 infection on post-tonsillectomy hemorrhage in pediatric patients, a potentially devastating complication. STUDY DESIGN: Retrospective cohort study. METHODS: The TriNetX database was queried for pediatric patients who underwent tonsillectomy and evaluated for outcomes of primary and secondary post-tonsillectomy hemorrhage. RESULTS: Among subjects 18 years and younger, 1226 were COVID-19 positive and 38,241 were COVID-19 negative in the perioperative period. There was statistically significant increased risk of bleeding with perioperative COVID-19 infection at postoperative days 1, 5, and 10. Additionally, when assessing the role of COVID-19 infection before or after surgery, the risk of bleeding remained statistically significant at all three time points, however these results did not suggest that infection before surgery confers more/less risk compared to infection after. CONCLUSION: The results of this investigation suggest that the presence of COVID-19 in the perioperative period may pose an increased risk for acute or delayed post tonsillectomy hemorrhage. This study employed a large, diverse population and is the first to address this clinical question.

Decannulation in Revision Pediatric Laryngotracheal Reconstruction.

OBJECTIVES: To evaluate how patient characteristics and surgical techniques influence the rate of and time to decannulation after pediatric revision laryngotracheal reconstruction. METHODS: The study was a retrospective cohort investigation of children with a history of laryngotracheal stenosis treated between 2008 and 2021 with revision open airway surgery. The primary outcome evaluated was decannulation. The secondary outcome analyzed was time to decannulation. RESULTS: Thirty-nine children were included in the study with median age 49 months; 61.5% were male. Children undergoing single stage revision surgery were far more likely to be decannulated (OR 6.25, 95% CI 1.33-45.97, p = 0.0343). Rolling logistic regression of the probability of decannulation stratified by time between open surgeries demonstrated significantly decreased chance of decannulation with reoperation within 6 months. Children managed with anterior/posterior grafting compared with a single graft were observed to have an increased time to decannulation, (HR 0.365, 95% CI 0.148-0.899, p = 0.005, Log-Rank). CONCLUSION: We observe that in the case of revision pediatric open airway surgery, chance of decannulation is improved when surgery is performed in a single stage as well as 6 months after the most recent procedure. Patients and families should be counseled that complex stenosis requiring double stage procedures or anterior/posterior grafting is associated with a decreased probability of decannulation and increased postoperative time with a tracheostomy, respectively. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1926-1932, 2024.

Pediatric Airway Balloon Dilation: Urge for Safety Redesign.

Airway balloons are widely used by otolaryngologists to treat laryngotracheal stenosis. We review an adverse event and interventions that may prevent similar occurrences. There are no other reports of similar incidents in the Food and Drug Administration Manufacturer and User Facility Device Experience. We implore Acclarent to redesign their airway balloon device to prevent accidental airway irrigation.

A retrospective analysis of pain and opioid usage in head and neck free flap reconstruction.

Objectives: Investigate opioid usage and postoperative pain in patients undergoing head and neck free flap surgery. Methods: A retrospective review of 100 consecutive patients undergoing head and neck free flap reconstruction at two academic centers was performed. Data captured included demographics, postoperative inpatient pain, pain at postoperative visits, morphine equivalent doses (MEDs) administration, medication history, and comorbidities. Data were analyzed using regression models, χ 2 tests, and student's t-tests. Results: Seventy-three percent of patients were discharged with opioid medication, with over half (53.4%) continuing to take opioids at their second postoperative visit, and over one-third (34.2%) continuing to take them around 4-month postoperatively. One out of every five (20.3%) opioid-naïve patients chronically took opioids postoperatively. There was a poor association between inpatient postoperative pain scores and daily MEDs administered (R 2 = 0.13, 0.17, and 0.22 in postoperative Days 3, 5, and 7, respectively). Neither preoperative radiotherapy nor postoperative complications were associated with an increase in opioid usage. Conclusions: For patients undergoing head and neck free flap operations, opioid medications are commonly used for postoperative analgesia. This practice may increase the chance an opioid-naïve patient uses opioids chronically. We found a poor association between MEDs administered and patient-reported pain scores, which suggests that standardized protocols aimed at optimizing analgesia while reducing opioid administration may be warranted. Level of Evidence: 3 (Retrospective cohort study).

Surgically treated pediatric tongue masses: A 20 Year review.

OBJECTIVE: Pediatric tongue lesions represent a rare, diverse group of pathologies related to congenital malformations, inflammatory changes, and neoplastic masses. We present the largest-to-date series of pediatric tongue lesions managed surgically. SETTING: Charts of all pediatric patients with a tongue lesion surgically treated at a regional children's hospital from February 1st, 1997 to August 30th, 2019 were reviewed. METHODS: After obtaining institutional review board approval, a retrospective review was completed of all pediatric patients with a tongue lesion surgically treated at a regional children's hospital from February 1st, 1997 through August 30th, 2019. Charts were evaluated for patient demographics as well as symptoms at presentation, surgical details, pathologic evaluation of the lesion, and rates of recurrence. Categorical variables were compared between various groups using Chi-square and/or Fisher's exact tests. Univariate and multivariable logistic regression analysis was performed unadjusted and adjusted to further explore these relationships. RESULTS: 159 patients were included in the study with ages distributed relatively even across infants (27.7%), children 1-5 years (27.7%), 6-10 years (23.3%), and greater than 10 years of age (21.4%). Patient/family reported race/ethnic background was most commonly Caucasian (34.8%) or Hispanic/Latino/Spanish Origin (34.0%) followed by Black or African American (21.3%). The most commonly reported symptoms were pain (23.3%), difficulty with oral intake (12.6%), bleeding (11.3%), and respiratory distress (11%). Patients with lesions of the base of tongue were significantly more likely to present with respiratory distress or difficulty with oral intake (p < 0.001). The likelihood of recurrence was observed to be higher with lesions managed in infancy (OR 3.85, CI 1.47-10.0, p = 0.005), those greater than 2 cm (OR 3.45, CI 1.34-8.71, p = 0.009), or with laser (OR 4.52, CI 1.25-15.00), p = 0.015). CONCLUSION: Pediatric patients with tongue lesions may present with a wide array of symptoms. Base of tongue lesions should be managed carefully as they are most likely to create barriers to the airway and oral intake. Larger lesions and those managed in infancy are at increased risk for recurrence.

Systematic Review of Slide Tracheoplasty Outcomes.

OBJECTIVE: To identify factors predicting success in slide tracheoplasty surgery at a regional children's hospital and compare with available published literature. MEASURES: Retrospective chart review comparing demographics (age, weight) and clinical (operative and hospital course, need for additional airway intervention) factors experienced with slide tracheoplasty. Findings were compared with a systematic review of published literature. RESULTS: Of the 16 tracheal stenosis patients in our cohort, 13 (81.3%) presented with an additional congenital or cardiovascular anomaly. When adjusted for cardiovascular anomalies, congenital tracheal stenosis patients had a mean age of 5.2 months (range 6 days-17 months), mean weight of 5.04 kg, and average ICU and hospital length of stay of 31.5 and 36.0 days, respectively. Tracheostomy was required for 4 patients and no early deaths were recorded. Of the 391 children in the grouped cohort, mean age and weight was older at 7.67 months and larger at 5.70 kg. Length of stay in both ICU and overall hospital course was 31.6 and 43.5 days, respectively. Mortality etiology for 44 patients was reported: 17 (38.6%) cardiac-related and 28 (63.6%) late mortalities. Our overall calculated mortality risk of 1.26 (P < .05) was lower than reported ratios of 2.0+. CONCLUSION: Despite the numerous institutional studies involving tracheal stenosis, mortality and surgical challenges remain high. Future studies with the inclusion of specific perioperative data can prove to further evaluate correlations between presentation characteristics and mortality.

Decannulation in Trisomy 21 patients undergoing laryngotracheal reconstruction.

BACKGROUND: Down Syndrome (DS) patients are more susceptible to either congenital or acquired subglottic stenosis (SGS). This often creates a multilevel airway obstruction and can lead to tracheostomy dependence early in life. As a result, they may require Laryngotracheal Reconstruction (LTR) to achieve decannulation. The primary objective of this study was to assess decannulation rates, time to decannulation and potential barriers to decannulation in DS patients undergoing LTR. METHODS: We performed a retrospective chart review from 2008 to 2021 of 193 children who underwent LTR for treatment for laryngotracheal stenosis at a stand-alone tertiary children's hospital. The relationship between clinical data and decannulation status was evaluated using multivariable logistic regression and Fisher exact tests. Time to decannulation analysis was performed using Kaplan Meier analysis and evaluated with log-rank and Cox proportional hazards regression. RESULTS: We determined that DS patients carry an inherit risk for decannulation failure compared to the general population (OR: 6.112, P = . 044, CI 1.046-35.730). Of the 8 patients with DS only three were decannulated. Overall, patients with Trisomy 21 had a significantly increased time to decannulation when compared to all LTR patients (P = .008, Log-rank). We found that these patients are more likely to have both suprastomal collapse (P = .0004, Fischer's Exact) and Tracheomalacia (P = .034, Fischer's Exact) compared to all other LTR patients. While post-operative tracheomalacia did not significantly affect decannulation failure (P = .056, Fischer's Exact) it did significantly prolong decannulation in all LTR patients (P = .018, Log-rank). CONCLUSION: Trisomy 21 patients are at an increased risk for decannulation failure. Our study illustrates that these poor outcomes are likely a result of conditions more commonly found in this cohort including: narrow tracheal caliber, tracheomalacia and hypotonia.

Malnutrition universal screening tool predicts postoperative complications following major head and neck cancer surgery.

BACKGROUND: Head and neck cancer patients are at risk for malnutrition, which can impact postoperative outcomes. This study evaluates the Malnutrition Universal Screening Tool (MUST) to predict outcomes in major head and neck surgeries. METHODS: A retrospective chart review included 275 major surgical procedures performed on 242 patients over the age of 18 years between May 2015 and May 2020. RESULTS: The majority of patients had a MUST score of zero (68.7%). Just under 17% scored 2 or greater indicating malnourishment. Having a MUST score of 2 or higher was associated with occurrence of a postoperative complication (p < 0.001). Patients with alcohol use disorder or depression were 5.2 (CI: 2.0-13.7, p = 0.001) and 2.75 (CI 1.1-7.0; p = 0.033) times more likely to develop a postoperative complication, respectively. CONCLUSIONS: Malnutrition and comorbidities were associated with complications in our surgical cohort. MUST is a novel tool to identify patients who may benefit from nutritional interventions.

Editorial Commentary: A Complex Network of Bony and Soft-Tissue Stabilizers-and Overall Limb Alignment-Determines Patellofemoral Stability.

Patellofemoral stability is maintained through a complex network of static and dynamic soft-tissue stabilizers, the osseous structure of the patella and trochlea, and overall limb alignment. Thus, determining the risk of recurrent patellar instability must account for as many of these factors as possible in the clinical decision-making process. The tibial tubercle-trochlear groove distance is the most common parameter used for this evaluation but may be limited because of methodologic issues and because this distance is an absolute value. Indices that incorporate other predisposing factors, including trochlear dysplasia, increase the accuracy of predicting recurrent patellar instability and can be used to generate a patient-specific treatment plan.

Design, synthesis and preclinical evaluation of bio-conjugated amylinomimetic peptides as long-acting amylin receptor agonists.

Pramlintide is an equipotent amylin analogue that reduces food intake and body weight in obese subjects and has been clinically approved as an adjunctive therapy for the treatment of adult diabetic patients. However, due to its extremely short half-life in vivo, a regimen of multiple daily administrations is required for achieving clinical effectiveness. Herein is described the development of prototypical long-acting pramlintide bioconjugates, in which pramlintide's disulfide-linked macrocycle was replaced by a cyclic thioether motif. This modification enabled stable chemical conjugation to a half-life extending antibody. In contrast to pramlintide (t1/2 < 0.75 h), bioconjugates 35 and 38 have terminal half-lives of ∼2 days in mice and attain significant exposure levels that are maintained up to 7 days. Single dose subcutaneous administration of 35 in lean mice, given 18-20 h prior to oral acetaminophen (AAP) administration, significantly reduced gastric emptying (as determined by plasma AAP levels). In a separate study, similar administration of 35 in fasted lean mice effected a reduction in food intake for up to 48 h. These data are consistent with durable amylinomimetic responses and provide the basis for further development of such long-acting amylinomimetic conjugates for the potential treatment of obesity and associated pathologies.

Adenoid stones, an unknown culprit in pediatric throat pain.

We present a case of a 12-year-old male who presented with complaints of nasal congestion, intermittent throat pain, and odynophagia. He was taken to the operating room for inferior turbinate reduction and adenoidectomy and found to have stones within adenoid crypts. Adenoidectomy resulted in resolution of the patient's throat pain and pain with swallowing. Not previously described in the literature, adenoid stones may represent an unrecognized etiology of odynophagia and throat pain in the pediatric population. Adenoidectomy should be considered for patients symptomatic from adenoid stones.

In vitro analysis of n-acetylcysteine (NAC) interference with the international normalized ratio (INR).

BACKGROUND: Previous literature suggests a laboratory interference of n-acetylcysteine (NAC) with prothrombin time (PT) and the international normalized ratio (INR). Early publications focused on this interaction in the setting of an acetaminophen overdose and evaluated the INR of patients receiving intravenous NAC. However, there is limited literature describing the concentration-effect relationship of NAC to INR measurement in the absence of acetaminophen-induced hepatotoxicity at therapeutic NAC concentrations. The purpose of the study is to quantify the degree of interference of NAC on INR values at therapeutic concentrations correlating to each infusion of the regimen (ex. bag 1: 550 mcg/mL, bag 2: 200 mcg/mL, bag 3: 35 mcg/mL, double bag 3: 70 mcg/mL) and at supratherapeutic concentrations in vitro. METHODS: Blood samples were obtained from study volunteers. Each blood sample was transferred into vials containing 0.3 mL buffered sodium citrate 3.2% and spiked with various concentrations of NAC for final concentrations of 0, 35, 70, 200, 550, 1000, 2000, and 4000 mcg/mL. The samples were centrifuged and tested to determine PT and INR on two separate machines: Siemens CS-2500 and Stago SN1114559. We would require a sample size of 6 to achieve a power of 80% and a level of significance of 1.7% (two-sided). Differences between INRs at varying concentrations were determined by Friedman's test. For multiple comparisons, post hoc analysis was performed using Wilcoxon signed-rank test with Bonferroni adjustment. Analyses were performed with SAS version 9.4 (SAS Institute, Cary, NC). RESULTS: Participants included 11 healthy subjects: 8 males, 3 females, median age 30 years (range 25 - 58). Median and interquartile ranges (IQR) INR for the baseline samples were 1.09 (IQR 1.05, 1.16) for Siemens and 1.03 (IQR 0.99, 1.11) for Stago analyzers. There was a significant difference in INR between the therapeutic concentrations (baseline, 35, 70,200, or 550 µg/mL) (Siemens p = .0008, Stago p < .0001). The 550 µg/mL concentration with the Siemens analyzer was the only one compared separately and found to be significantly greater than the baseline (1.07 vs 1.22, p = .02). For the Stago analyzer the 200 µg/mL and 500 µg/mL were compared and found to be significantly different from baseline (1.00 vs 1.07 and 1.19, adjusted p = .02 and p = .03, respectively). The largest INR increase seen was in one subject from a baseline of 1.07-1.32 with the 550 µg/mL concentration. Increases in concentrations to supratherapeutic levels resulted in a statistically significant non-linear increase in INR for all concentrations (Siemens p < .0001, Stago p < .0001). All of these concentrations were found to be significantly different from baseline (all adjusted p < .05). CONCLUSION: Although it was found that at therapeutic concentrations the in vitro presence of NAC affects INR measurements on two different machines, the change is of little clinical relevance. Supratherapeutic concentrations of NAC affect INR significantly, but the clinical utility of those results is limited by the rarity of those concentrations being measured.

Laryngomalacia in the Premature Neonate.

Laryngomalacia is the most common cause of stridor in newborns. Affected patients may present with noisy breathing, a classic high-pitched inspiratory stridor that worsens with feeding. While the exact etiology remains unclear, the condition is characterized by softening of the supraglottic structures, including the epiglottis, aryepiglottic folds, and arytenoid cartilages. The condition is most often self-limited and requires expectant management. However, in some infants, severe disease, including failure to thrive or respiratory distress, may require medical or even surgical intervention. When caring for premature neonates, special care is required to evaluate for synchronous airway lesions.

Pd(II) complexes with chelating N-(1-alkylpyridin-4(1H)-ylidene)amide (PYA) ligands: Synthesis, characterization and evaluation of anticancer activity.

The bidentate N-(1-Alkylpyridin-4(1H)-ylidene)amide (PYA) pro-ligands [H2LBn][Cl]2 (2), and [H2LMe][TfO]2 (3) were prepared by simple alkylation reactions of the known compound, N,N-di(pyridin-4-yl)oxalamide (H2L, 1). The Pd(II) complexes, [Pd(LBn)2][Cl]2 (4), [Pd(LMe)2][Cl][TfO] (5), Pd(LBn)Cl2 (6) and Pd(LMe)Cl2 (7) were synthesized through reactions between these pro-ligands and suitable Pd(II) substrates in the presence of base. The molecular structures of 3 and 6 were obtained by single crystal X-ray structure determinations. Studies of the experimental and computational DNA binding interactions of the compounds 1-7 revealed that overall 4 and 6 have the largest values for the binding parameters Kb and ΔGbo. The results showed a good correlation with the steric and electronic parameters obtained by quantitative structure activity relationship (QSAR) studies. In-vitro cytotoxicity studies against four different cell lines showed that the human breast cancer cell lines MCF-7, T47D and cervical cancer cell line HeLa had either higher or similar sensitivities towards 4, 6 and 2, respectively, compared to cisplatin. In general, the cytotoxicity of the compounds, represented by IC50 values, decreased in the order 4 > 6 > 2 > 5 > 3 > 1 > 7 in cancer cell lines. Apoptosis contributed significantly to the cytotoxic effects of these anticancer agents as evaluated by apoptosis studies.

Pediatric tracheostomy surveillance.

We report an unusual case of a 14-month-old ex-28 week, ventilator-dependent male with a history of bronchopulmonary dysplasia and tracheostomy at 2 months of age. Lost to follow-up, at age 9 months, he presented to the emergency department with worsening respiratory distress. The patient was taken to the operating room at which time direct visualization of the airway demonstrated a mass filling the entire glottic inlet without supraglottic or pharyngeal mucosal attachments. The solid, nonvascular, mass appeared to be emanating from a suprastomal site. Excision proved to relieve the airway obstruction and postoperatively the patient has thrived.

Editorial Commentary: Preoperative Exercise, Workers' Compensation, Diabetes, Lateral Extra-Articular Tenodesis, and Return to Sport Determine Patient Satisfaction After Anterior Cruciate Ligament Reconstruction.

Patient-reported outcome measures (PROMs) have been developed and used as the primary determinant of successful patient-centered results. The patient acceptable symptomatic state delineates an absolute value for PROMs indicating that patients are satisfied with their outcome. When this metric is used for anterior cruciate ligament reconstruction, patients reach a satisfactory outcome at between 6 and 8 months postoperatively, and more than 90% reach a satisfactory outcome at 12 months. Preoperative variables such as preoperative exercise, Workers' Compensation, and diabetes impact patient outcomes, whereas preoperative PROMs and use of the anteromedial portal technique for femoral tunnel drilling have a limited impact on satisfaction. Iliotibial band tenodesis shows a large impact on satisfactory outcomes; however, this result may be affected by patient demographic issues (selection bias). Ultimately, a "satisfactory" outcome is a very general term and may not necessarily apply to active athletes desiring a return to competitive sport. Thus, the patient acceptable symptomatic state should be interpreted in combination with a surgeon's experience. Ultimately, the success of a surgical procedure could be determined, in large part, based on the patient's individual preoperative expectations.

Conjugation of a peptide to an antibody engineered with free cysteines dramatically improves half-life and activity.

The long circulating half-life and inherently bivalent architecture of IgGs provide an ideal vehicle for presenting otherwise short-lived G-protein-coupled receptor agonists in a format that enables avidity-driven enhancement of potency. Here, we describe the site-specific conjugation of a dual agonist peptide (an oxyntomodulin variant engineered for potency and in vivo stability) to the complementarity-determining regions (CDRs) of an immunologically silent IgG4. A cysteine-containing heavy chain CDR3 variant was identified that provided clean conjugation to a bromoacetylated peptide without interference from any of the endogenous mAb cysteine residues. The resulting mAb-peptide homodimer has high potency at both target receptors (glucagon receptor, GCGR, and glucagon-like peptide 1 receptor, GLP-1R) driven by an increase in receptor avidity provided by the spatially defined presentation of the peptides. Interestingly, the avidity effects are different at the two target receptors. A single dose of the long-acting peptide conjugate robustly inhibited food intake and decreased body weight in insulin resistant diet-induced obese mice, in addition to ameliorating glucose intolerance. Inhibition of food intake and decrease in body weight was also seen in overweight cynomolgus monkeys. The weight loss resulting from dosing with the bivalently conjugated dual agonist was significantly greater than for the monomeric analog, clearly demonstrating translation of the measured in vitro avidity to in vivo pharmacology.