Polymer-Tethered Quenched Fluorescent Probes for Enhanced Imaging of Tumor-Associated Proteases.

Fluorescence-based contrast agents enable real-time detection of solid tumors and their neovasculature, making them ideal for use in image-guided surgery. Several agents have entered late-stage clinical trials or secured FDA approval, suggesting they are likely to become the standard of care in cancer surgeries. One of the key parameters to optimize in contrast agents is molecular size, which dictates much of the pharmacokinetic and pharmacodynamic properties of the agent. Here, we describe the development of a class of protease-activated quenched fluorescent probes in which a N-(2-hydroxypropyl)methacrylamide copolymer is used as the primary scaffold. This copolymer core provides a high degree of probe modularity to generate structures that cannot be achieved with small molecules and peptide probes. We used a previously validated cathepsin substrate and evaluated the effects of length and type of linker, as well as the positioning of the fluorophore/quencher pair on the polymer core. We found that the polymeric probes could be optimized to achieve increased overall signal and tumor-to-background ratios compared to the reference small molecule probe. Our results also revealed multiple structure-activity relationship trends that can be used to design and optimize future optical imaging probes. Furthermore, they confirm that a hydrophilic polymer is an ideal scaffold for use in optical imaging contrast probes, allowing a highly modular design that enables efficient optimization to maximize probe accumulation and overall biodistribution properties.

Distribution of 35 Polycyclic Aromatic Hydrocarbons in Pine Needle Samples from Selected Locations in the Republic of Korea.

Polycyclic aromatic hydrocarbons (PAHs), dust, and wax were measured in pine needles, and PAHs were also measured in surface soil. Pearson correlation analysis was performed between the analytical values. The main compounds responsible for the increase in total PAHs were non-carcinogenic phenanthrene and fluoranthene. Therefore, the % content of carcinogenic PAHs decreased with a slope = -0.037 (r = 0.47, p < 0.01), as the total PAH concentration in pine needles increased. Correlations between individual PAHs in pine needles and surface soil were very high when only low-number ring PAHs (2R- and 3R-PAHs) were statistically analyzed and significant when only high-number ring PAHs were statistically analyzed. Low-number ring PAH mainly moves in the gas phase and diffuses into the wax layer, so it was found to be statistically significant with the wax content of pine needles. High-number ring PAHs showed a high correlation with the amount of dust in pine needles because they mainly attached to dust particles and accumulated on the surface of pine needles. The ratios of fluoranthene/pyrene and methylphenanthrene/phenanthrene for predicting the origin of atmospheric PAHs have also been proven valid for pine needles.

Polymer-tethered quenched fluorescent probes for enhanced imaging of tumor associated proteases.

Fluorescence-based contrast agents enable real-time detection of solid tumors and their neovasculature, making them ideal for use in image-guided surgery. Several agents have entered late-stage clinical trials or secured FDA approval, suggesting they are likely to become standard of care in cancer surgeries. One of the key parameters to optimize in contrast agent is molecular size, which dictates much of the pharmacokinetic and pharmacodynamic properties of the agent. Here, we describe the development of a class of protease-activated quenched fluorescent probes in which a N-(2-hydroxypropyl)methacrylamide copolymer is used as the primary scaffold. This copolymer core provides a high degree of probe modularity to generate structures that cannot be achieved with small molecules and peptide probes. We used a previously validated cathepsin substrate and evaluated the effects of length and type of linker as well as positioning of the fluorophore/quencher pair on the polymer core. We found that the polymeric probes could be optimized to achieve increased over-all signal and tumor-to-background ratios compared to the reference small molecule probe. Our results also revealed multiple structure-activity relationship trends that can be used to design and optimize future optical imaging probes. Furthermore, they confirm that a hydrophilic polymer is an ideal scaffold for use in optical imaging contrast probes, allowing a highly modular design that enables efficient optimization to maximize probe accumulation and overall biodistribution properties.

Mercury monitoring in the coastal areas of the Republic of Korea using the black-tailed gull egg as an indicator.

In the southeast and east coasts of the Republic of Korea, it is essential to monitor mercury accumulation in coastal organisms in view of the higher mercury distribution in sediments and human samples. However, mercury pollution monitoring in organisms, especially higher trophic-level organisms that can exhibit high mercury accumulation, is limited. Here, we examined the applicability of the eggs of the black-tailed gull (Larus crassirostris), which belongs to a high trophic level, for mercury monitoring in coastal areas. Breeding sites were selected in West, Southeast, and East Seas with different mercury concentrations in other matrices (sediment and biological samples of residents). The 5-year mean total mercury concentration in eggs collected during the breeding seasons from 2016 to 2020 was lower in Baengnyeongdo (705 ± 81 ng/g dry weight (dry), West Sea) than in Hongdo (1,207 ± 214 ng/g dry, Southeast Sea) and Ulleungdo (1,095 ± 95 ng/g dry, East Sea). The different patterns of mercury concentration in gull eggs among the breeding sites was consistent with those in the other matrices among the coastal areas. These results support the applicability of the black-tailed gull egg as an indicator for establishing a monitoring framework in the coastal areas of the Republic of Korea.

Development of Oxadiazolone Activity-Based Probes Targeting FphE for Specific Detection of Staphylococcus aureus Infections.

Staphylococcus aureus (S. aureus) is a major human pathogen that is responsible for a wide range of systemic infections. Since its propensity to form biofilms in vivo poses formidable challenges for both detection and treatment, tools that can be used to specifically image S. aureus biofilms are highly valuable for clinical management. Here, we describe the development of oxadiazolone-based activity-based probes to target the S. aureus-specific serine hydrolase FphE. Because this enzyme lacks homologues in other bacteria, it is an ideal target for selective imaging of S. aureus infections. Using X-ray crystallography, direct cell labeling, and mouse models of infection, we demonstrate that oxadiazolone-based probes enable specific labeling of S. aureus bacteria through the direct covalent modification of the FphE active site serine. These results demonstrate the utility of the oxadizolone electrophile for activity-based probes and validate FphE as a target for the development of imaging contrast agents for the rapid detection of S. aureus infections.

Risk Factors Associated with Postoperative CSF Leak in Extrasellar Tumors.

Objective While postoperative cerebrospinal fluid (CSF) leak rates of pituitary tumors have been frequently studied, there are fewer studies examining postoperative CSF leak rates for extrasellar tumors. The purpose of this study was to identify risk factors for the development of postoperative CSF leak in patients undergoing endoscopic surgery for extrasellar tumors. Methods A retrospective chart review was done for patients who underwent endoscopic resection for extrasellar tumors between 2008 and 2020. Age, gender, tumor type, tumor location, tumor size, reconstruction technique, medical comorbidities, and other potential risk factors were identified. Data was analyzed to identify significant risk factors for development of postoperative CSF leak. Results There were 100 patients with extrasellar tumors who developed intraoperative CSF leaks. Seventeen patients (17%) developed postoperative CSF leaks. Leaks occurred at a median of 2 days following surgery (range 0-34 days). Clival tumors had a significantly higher incidence of postoperative leak than those in other sites ( p < 0.05). There were no significant differences in other locations, body mass index, tumor size, reconstruction technique, medical comorbidities, or other factors. There were nearly twice as many intraoperative grade III leaks in those who developed postoperative CSF leak, but this was not statistically significant ( p = 0.12). Conclusion Extrasellar tumors, particularly clival tumors, have a higher rate of postoperative CSF leak than pituitary tumors. Prophylactic lumbar drains can be considered for patients at high risk for developing postoperative CSF leak.

Current and Emerging Therapies for Chronic Subjective Tinnitus.

IMPORTANCE: Chronic subjective tinnitus, the perception of sound without an external source for longer than six months, may be a greatly debilitating condition for some people, and is associated with psychiatric comorbidities and high healthcare costs. Current treatments are not beneficial for all patients and there is a large need for new therapies for tinnitus. OBSERVATIONS: Unlike rarer cases of objective tinnitus, chronic subjective tinnitus often has no obvious etiology and a diverse pathophysiology. In the absence of objective testing, diagnosis is heavily based on clinical assessment. Management strategies include hearing aids, sound masking, tinnitus retraining therapy, cognitive behavioral therapy, and emerging therapies including transcranial magnetic stimulation and electrical stimulation. CONCLUSIONS AND RELEVANCE: Although current treatments are limited, emerging diagnostics and treatments provide promising avenues for the management of tinnitus symptoms.

International Multicenter Study of Clinical Outcomes of Sinonasal Melanoma Shows Survival Benefit for Patients Treated with Immune Checkpoint Inhibitors and Potential Improvements to the Current TNM Staging System.

Objectives Sinonasal mucosal melanoma (SNMM) is an extremely rare and challenging sinonasal malignancy with a poor prognosis. Standard treatment involves complete surgical resection, but the role of adjuvant therapy remains unclear. Crucially, our understanding of its clinical presentation, course, and optimal treatment remains limited, and few advancements in improving its management have been made in the recent past. Methods We conducted an international multicenter retrospective analysis of 505 SNMM cases from 11 institutions across the United States, United Kingdom, Ireland, and continental Europe. Data on clinical presentation, diagnosis, treatment, and clinical outcomes were assessed. Results One-, three-, and five-year recurrence-free and overall survival were 61.4, 30.6, and 22.0%, and 77.6, 49.2, and 38.3%, respectively. Compared with disease confined to the nasal cavity, sinus involvement confers significantly worse survival; based on this, further stratifying the T3 stage was highly prognostic ( p < 0.001) with implications for a potential modification to the current TNM staging system. There was a statistically significant survival benefit for patients who received adjuvant radiotherapy, compared with those who underwent surgery alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI]: 0.57-0.96, p = 0.021). Immune checkpoint blockade for the management of recurrent or persistent disease, with or without distant metastasis, conferred longer survival (HR = 0.50, 95% CI: 0.25-1.00, p = 0.036). Conclusions We present findings from the largest cohort of SNMM reported to date. We demonstrate the potential utility of further stratifying the T3 stage by sinus involvement and present promising data on the benefit of immune checkpoint inhibitors for recurrent, persistent, or metastatic disease with implications for future clinical trials in this field.

Is lobectomy sufficient for multifocal papillary thyroid microcarcinoma?

IMPORTANCE: Multifocal papillary thyroid microcarcinoma (PTMC) has been associated with a higher incidence of lymph node involvement, bilateral involvement, and extrathyroidal extension compared to unifocal papillary thyroid cancer (PTC). OBJECTIVE: To describe the incidence and determinants of survival for patients with multifocal PTMC using the Surveillance, Epidemiology, and End Result (SEER) database. DESIGN, SETTING, PARTICIPANTS: The SEER registry was utilized to calculate survival trends for patients with PTMC between 2010 and 2015. Patient data was then analyzed with respect to age, sex, race, multifocality, and types of surgery rendered. MAIN OUTCOMES AND MEASURES: Overall Survival (OS) and Disease Specific Survival (DSS). RESULTS: 22,283 cases of papillary thyroid microcarcinoma (T1a N0 M0) were identified. The cohort was composed of 82.6 % females, and about 82 % of patients were of white race. The mean age at diagnosis was 51.9 years. Multifocal PTMC was present in 32.2 % of the tumors (n = 7186). 73.9 % of patients underwent total thyroidectomy and 23.0 % received lobectomy. OS at 2 and 5 years was 98 % and 95 %, respectively. Multivariate analysis revealed that age, sex, and multifocality were determinants of OS. Only age was a determinant of DSS. Kaplan-Meier survival analysis revealed that multifocal PTMC had similar mean OS between lobectomy and total thyroidectomy patients (69.59 months versus 69.82 months). CONCLUSIONS AND RELEVANCE: PTMC has a good prognosis. Our analysis revealed that age was a determinant of OS and DSS; sex and multifocality were also prognosticators for OS. The type of surgery, whether lobectomy or total thyroidectomy, was not a determinant of survival in multifocal PTMC.

Development of Oxadiazolone Activity-Based Probes Targeting FphE for Specific Detection of S. aureus Infections.

Staphylococcus aureus is a major human pathogen responsible for a wide range of systemic infections. Since its propensity to form biofilms in vivo poses formidable challenges for both detection and treatment, tools that can be used to specifically image S. aureus biofilms are highly valuable for clinical management. Here we describe the development of oxadiazolonebased activity-based probes to target the S. aureus-specific serine hydrolase FphE. Because this enzyme lacks homologs in other bacteria, it is an ideal target for selective imaging of S. aureus infections. Using X-ray crystallography, direct cell labeling and mouse models of infection we demonstrate that oxadiazolone-based probes enable specific labeling of S. aureus bacteria through the direct covalent modification of the FphE active site serine. These results demonstrate the utility of the oxadizolone electrophile for activity-based probes (ABPs) and validate FphE as a target for development of imaging contrast agents for the rapid detection of S. aureus infections.

Temporal and spatial trends of chlorinated paraffins and organophosphate flame retardants in black-tailed gull (Larus crassirostris) eggs.

In this study, eggs of black-tailed gull (Larus crassirostris), a top trophic level predator of marine ecosystem were, for the first time, monitored to assess the temporal and spatial trends of emerging pollutants in South Korea. Two Island regions, namely, Baekryeong-do (Site A) and Hong-do (Site B) were investigated from 2012 to 2018, and the total levels of short chain chlorinated paraffins (SCCPs), medium chain CPs (MCCPs), and organophosphate flame retardants (OPFRs) for both Site A and B were 1180-2931 and 694-2023 ng/g lipid weight (lw), 1287-4898 and 1034-3075 ng/g lw, and 203-499 and 233-409 ng/g lw, respectively. The time-trends of the concentration of pollutants showed an increasing tendency from 2012 to 2018, with the levels predicted to be doubled within three years, following the results of regression analysis. A shift in temporal-trends from shorter to longer chain CPs was noted, suggesting the effect of industrial-related contamination. Especially, significantly high levels of CPs and OPFRs were found in the site adjacent to China, which is reasonable as China is the largest producer and consumer of FRs and plasticizers worldwide. This study is valuable to understand the temporal increment of emerging pollutants as the alternatives of phased-out FRs and plasticizers, while raising the need for continuous environmental management.

Contrast-Induced Sialadenitis of the Sublingual Glands.

Contrast-induced sialadenitis (CIS) is a rare, delayed pseudoallergic reaction from iodine containing contrast. Previously reported cases of CIS demonstrated that the two major salivary glands (parotid and submandibular) can be affected. The initial encounter of this entity can raise alarms to physicians as the differential diagnoses include serious infectious and inflammatory conditions such as Ludwig's angina and angioedema. Subsequently, it may lead to unnecessary testing and increased healthcare cost. Here we present a 60-year-old male who presented with bilateral sublingual gland swelling following exposure to iodinated contrast. With timely diagnosis by the otolaryngologist, the patient received conservative management that led to a full resolution within a few days. To date, this is the first case of CIS only involving the sublingual glands. We conclude that CIS can involve any of the major salivary glands.

Simultaneous determination of PCBs, OCPs and PAHs in mussel by ultrasound-assisted cloudy extraction and gas chromatography-tandem mass spectrometry.

A method for the simultaneous determination in mussel of 8 polychlorinated biphenyls (PCBs), 23 organochlorine pesticides (OCPs), and 35 polycyclic aromatic hydrocarbons (PAHs), including alkyl-PAHs, was optimised using ultrasound-assisted cloudy extraction and gas chromatography-tandem mass spectrometry (GC-MS/MS). Optimal selection of the extraction solvent and the dispersing solvent contributed to a high extraction yield and a clean extract. The ranges of the lower limits of detection of PCBs, OCPs and PAHs were 0.012-0.058, 0.01-0.29 and 0.01-0.5 µg kg-1, respectively. The feasibility of the proposed method was validated by analysing standard reference materials of mussel with satisfactory results. The precision achieved by this method was in the range of 0.677-2.69% (PCBs), 1.14-6.60% (OCPs) and 0.694-7.46% (PAHs), and its accuracy was in the range of 101-104% (PCBs), 99.6-106% (OCPs) and 101-110% (PAHs). The advantages of the method include the simultaneous measurement of 66 analytes and the simplicity, low cost and high sensitivity of the procedure. When the proposed method was used to analyse the target compounds in 11 mussel samples, the analytical results displayed a concentration range of 0.41-0.45 µg kg-1 for PCBs, 0.26-6.49 µg kg-1 for OCPs, and 3.48-30.69 µg kg-1 for PAHs.

Surgical outcomes of simultaneous cochlear implantation with subtotal petrosectomy.

OBJECTIVE: To evaluate the surgical outcomes of simultaneous cochlear implantation (CI) with subtotal petrosectomy (SP). METHODS: Medical records of thirty-one patients (31 ears) who underwent simultaneous CI with SP in two tertiary referral centers for management of profound hearing loss secondary to chronic suppurative otitis media, cholesteatoma, previous open cavity, temporal bone fracture, and temporal bone irradiation were retrospectively analyzed. Pre and postoperative speech performances and related complications requiring surgical correction were evaluated. RESULTS: Significant improvement in postoperative speech performance was observed in all 31 patients compared to preoperative result. Of the 31 patients, complications occurred in three patients (9.6%). One patient exhibited the breakdown of blind sac closure of the external auditory canal and two others exhibited the migration of the receiver-stimulator cochlear implant. The migrations occurred despite tie-down fixation of the device to the skull. The migrated devices were repositioned using revision surgery. CONCLUSIONS: Simultaneous CI with SP is an effective and safe surgical method with relatively low complication incidence. However, particular attention should be paid to prevent certain complications. The receiver-stimulator may be predisposed to migrate to abnormal position because it can be placed with lack of tight subperiosteal support at a more superior or posterior location of the skull where the skull curvature changes abruptly than can conventional CI using limited mastoidectomy and posterior tympanotomy approach.

Analysis of Risk Factors for Myringosclerosis Formation after Ventilation Tube Insertion.

BACKGROUND: This study examined possible risk factors for myringosclerosis formation after ventilation tube insertion (VTI). METHODS: A retrospective study was performed in a single tertiary referral center. A total of 582 patients who underwent VTI were enrolled in this study. Patients were divided into two groups based on the presence or absence of myringosclerosis: MS+ and MS-. Characteristics of patients were collected through medical chart review; these included age, gender, nature and duration of effusion, type of ventilation tube (VT), duration and frequency of VTI, incidence of post-VTI infection, incidence of intraoperative bleeding, and presence of postoperative perforation. Incidences of risk factors for myringosclerosis and the severity of myringosclerosis in association with possible risk factors were analyzed. RESULTS: Myringosclerosis developed in 168 of 582 patients (28.9%) after VTI. Patients in the MS+ group had an older mean age than those in the MS- group. The rates of myringosclerosis were higher in patients with older age, serous otitis media, type 2 VT, post-VTI perforation, and frequent VTI. However, there were no differences in occurrence of myringosclerosis based on gender, duration of effusion, duration of VT placement, incidence of post-VTI infection, or incidence of intraoperative bleeding. The severity of myringosclerosis was associated with the duration of effusion and frequency of VTI. CONCLUSION: Older age, serous effusion, type 2 VT, presence of post-VTI perforation, and frequent VTI may be risk factors for myringosclerosis after VTI; the severity of myringosclerosis may vary based on the duration of effusion and frequency of VTI.

Cochlear Implantation in Patients with Chronic Suppurative Otitis Media: Surgical Outcomes and a Management Algorithm.

BACKGROUND: Chronic suppurative otitis media (CSOM) was considered as a contraindication of cochlear implantation (CI) in the past. Recently, various surgical options have been adopted for CI in CSOM patients with showing a low complication rate. OBJECTIVES: To evaluate surgical outcomes of CI in patients with CSOM and to propose a management algorithm for those patients. METHODS: Thirty-six consecutive patients with CSOM who underwent single stage or staged CI were enrolled. Speech performance, including Categories of Auditory Performance (CAP) test and sentence score, and complications were retrospectively analyzed. RESULTS: The average follow-up was 3.1 years (range 0.5-9.2 years). Postoperative median CAP and sentence scores were 6 and 78%, respectively. Three (8.3%) of the 36 patients had postoperative complications. One experienced breakdown of the ear canal closure. Recurrence of the pars tensa retraction was observed in another patient with adhesive otitis media who underwent CI and cartilage tympanoplasty as a single stage operation. Electrode extrusion occurred in another patient who underwent staged CI with maintenance of a previous open cavity. Subtotal petrosectomy and cavity obliteration were used to manage the latter 2 complications. All implant patients with good mastoid pneumatization exhibited no complications. There were no significant differences in postoperative speech performance and complication rates between single stage CI and staged CI. Based on these current findings, a management algorithm was proposed according to type of CSOM, presence of open cavity, and mastoid pneumatization. CONCLUSIONS: Patients with CSOM show good postoperative speech performance after CI. Proper surgical options according to type of CSOM, presence of open cavity, and mastoid pneumatization may help in reducing complications.

Utilization of black-tailed gull (Larus crassirostris) eggs for monitoring of mercury levels in coastal areas of South Korea: Preliminary study.

Studies on the monitoring of mercury accumulation using high trophic-level predators of the marine ecosystem have been scarce in South Korea. In this study, we compared the mercury concentrations of the eggs of the black-tailed gulls, a higher-order predator, breeding in two coastal areas. Breeding sites with varying mercury concentrations in land-origin freshwater fish and freshwater and marine sediments were selected in the southeastern (Hongdo Island) and western (Baengnyeongdo Island) seas. The 5-year mean total mercury concentration in eggs collected during the breeding seasons from 2012 to 2016 was higher in those collected from Hongdo than in those collected from Baengnyeongdo. This difference in mercury concentration in eggs was observed for each year. In addition, the total mercury concentration in eggs was consistently higher on Hongdo, which also had higher mercury pollution, than on Baengnyeongdo Island. These results support the suitability of black-tailed gull eggs for monitoring of mercury pollution.

Readmissions after endoscopic skull base surgery: associated risk factors and prevention.

BACKGROUND: Unplanned readmissions within 30 days of discharge is a quality measure introduced by the Centers for Medicare Services. This measure has been used to rate hospital quality and also to penalize hospitals for excess readmissions. It has been hypothesized that shorter hospital stays and fewer readmissions are associated with endoscopic skull base procedures. In this study we analyze endoscopic skull base procedures performed at our institution over a 10-year period to identify rates and factors associated with readmissions after endoscopic skull base surgery. METHODS: A retrospective chart review was performed at a tertiary care academic medical center identifying patients who underwent endoscopic skull base surgery over the past 10 years. Data on patient demographics and tumor variables, as well as patient variables such as body mass index (BMI), revision surgery, history of skull base radiation, medical comorbidities, intraoperative cerebrospinal fluid (CSF) leaks, and postoperative CSF leaks, were recorded. RESULTS: Eight hundred thirty-three patients were included in our study. Sixty-one patients (7.3%) were readmitted a total of 66 times within 30 days. The most common reasons were as follows: hyponatremia (n = 18); CSF leak (n = 17); epistaxis (n = 3); diabetes insipidus (n = 3); rhinorrhea (n = 3); as well as other reasons. Statistical analysis revealed that the presence of intraoperative CSF leak was the only statistically significant variable associated with increased rate of readmissions within 30 days of discharge (p < 0.001). CONCLUSION: Presence of intraoperative CSF leak was the only statistically significant variable associated with an increased risk for readmission after surgery. Other tumor and patient variables were not associated with an increased risk of readmission within 30 days.

The most reliable time point for intact parathyroid hormone measurement to predict hypoparathyroidism after total thyroidectomy with central neck dissection to treat papillary thyroid carcinoma: a prospective cohort study.

PURPOSE: We assessed the optimal time for intact parathyroid hormone (iPTH) measurement for early detection of post-total thyroidectomy (TT) hypocalcemia in patients with papillary thyroid carcinoma (PTC). METHODS: In this single-center prospective cohort study, 143 patients who underwent TT with central neck dissection with or without lateral neck dissection for PTC were included. Biochemical profiles including iPTH, corrected total calcium, and ionized calcium within 24 h after surgery were analyzed. RESULTS: The 4-h postoperative iPTH was the most reliable predictor of post-TT transient or permanent hypoparathyroidism (cutoff for hypocalcemia was 3.75 pg/mL, AUC = 0.885, P < 0.001, sensitivity 81.6%, specificity 86.0%; cutoff for permanent hypocalcemia was 2.48 pg/mL, AUC = 0.819, P < 0.001, sensitivity 100%, specificity 57.8% calculated using ROC curves). CONCLUSIONS: The 4-h postoperative iPTH can most accurately predict hypoparathyroidism after TT with central neck dissection to treat PTC and facilitate the early discharge of low-risk postoperative hypoparathyroidism patients and decrease unnecessary overnight observation and calcium supplementation.