Improved Radiosynthesis and Automation of [11C]2-(2,6-Difluoro-4-((2-(N-methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([11C]K2) for Positron Emission Tomography of the Glutamate α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid (AMPA) Receptor.

A new automated radiosynthesis of [11C]2-(2,6-difluoro-4-((2-(N-methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([11C]K2), a radiopharmaceutical for the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, is reported. Although manual syntheses have been described, these are unsuitable for routine production of larger batches of [11C]K2 for (pre)clinical PET imaging applications. To meet demands for the imaging agent from our functional neuroimaging collaborators, herein, we report a current good manufacturing practice (cGMP)-compliant synthesis of [11C]K2 using a commercial synthesis module. The new synthesis is fully automated and has been validated for clinical use. The total synthesis time is 33 min from end of bombardment, and the production method provides 2.66 ± 0.3 GBq (71.9 ± 8.6 mCi) of [11C]K2 in 97.7 ± 0.5% radiochemical purity and 754.1 ± 231.5 TBq/mmol (20,382.7 ± 6256.1 Ci/mmol) molar activity (n = 3). Batches passed all requisite quality control testing confirming suitability for clinical use.

Extratunical grafting for minimally invasive management of complex Peyronie's disease deformities.

BACKGROUND: Penile deformities due to Peyronie's Disease (PD) often significantly impair men's sexual health and quality of life. AIM: In this article we discuss the extratunical graft (ETG) procedure as a management strategy for PD patients with hourglass or indent penile deformities. METHODS: We compiled descriptions of surgical techniques and performed a review of the literature regarding ETG for PD. OUTCOMES: The ETG procedure appears to have promising results in the management of indent/hourglass deformity of PD. RESULTS: The findings of this review of the literature demonstrate that ETG is a safe and effective reconstructive technique for penile deformity with minimal side effects. CLINICAL IMPLICATIONS: We recommend utilizing ETG with or without plication for PD patients with indent or hourglass deformities. STRENGTHS AND LIMITATIONS: Strengths of ETG are the improvement in patients with tunical indents and hourglass deformities secondary to PD. Additionally, patients who underwent ETG maintained sexual function given no significant change in penile length and intact erectile function. Limitations, however, are that the procedure is relatively new, and data are limited to small cohorts. CONCLUSION: The ETG procedure is a safe and effective for management of complex PD in the short- and intermediate-term follow-up cohort.

Does Positioning During Oral and Maxillofacial Surgery Operations Influence the Development of Upper Extremity Peripheral Neuropathy?

BACKGROUND: Controversy exists regarding the role of specific etiology and mitigating factors in perioperative upper extremity peripheral neuropathy (PUN) development during oral and maxillofacial surgery (OMS) procedures. PURPOSE: The purpose of this study was to measure the association between upper extremity (UE) positioning and developing PUN in OMS operations. STUDY DESIGN, SETTING, SAMPLE: The investigators implemented a retrospective cohort study. Patients referred to the Department of Oral and Maxillofacial Surgery at Jefferson Health who underwent orthognathic, telegnathic, or free flap surgery from April 2017 through December 2021 were identified. Exclusion criteria were age less than 13, revision surgery, ablative case without free flap reconstruction, incomplete medical record, pre-existing neuropathy, and UE position other than tucked or abducted. PREDICTOR VARIABLE: The predictor variable was UE position during surgery, which had 2 levels-tucked or abducted. MAIN OUTCOME VARIABLE: The outcome variable was self-reported development of PUN, defined as new sensory and/or motor deficit in a nonoperated extremity diagnosed within 48 hours of surgery. COVARIATES: Demographic covariates included age, gender, and race. Perioperative covariates included American Society of Anesthesiologists physical status and body mass index (BMI). The operative covariate was general anesthesia (GA) duration. ANALYSES: Descriptive statistics were calculated. Shapiro-Wilk test was used to assess normality of the sample. Categorical variables were analyzed with Fisher's exact test. Continuous variables were analyzed with Mann-Whitney U test. Significance was defined at P < .05. RESULTS: Of the 432 patients identified, 342 met inclusion criteria. Median (interquartile range) ages for the abducted and tucked cohorts were 40 (31) and 34 (28) years, respectively (P < .01). Males comprised 55.4% (n = 41) and 54.1% (n = 145) of abducted and tucked groups, respectively (P = .9). PUN frequency was 6.8% (n = 5) for abducted subjects and 3.7% (n = 10) for tucked subjects (relative risk 1.8, 95% confidence interval [0.7, 5.1]; P = .33). PUN was associated with gender (P = .01), American Society of Anesthesiologists status (P = .03), BMI (P = .01), and GA duration (P < .01) on bivariate analysis. When adjusting for covariates, only GA duration (P < .01) and BMI (P = .03) were associated with PUN development. CONCLUSION AND RELEVANCE: The findings suggest that PUN development during OMS procedures was not associated with UE position.

Watershed analysis of urban stormwater contaminant 6PPD-Quinone hotspots and stream concentrations using a process-based ecohydrological model.

Coho salmon (Oncorhynchus kisutch) are highly sensitive to 6PPD-Quinone (6PPD-Q). Details of the hydrological and biogeochemical processes controlling spatial and temporal dynamics of 6PPD-Q fate and transport from points of deposition to receiving waters (e.g., streams, estuaries) are poorly understood. To understand the fate and transport of 6PPD and mechanisms leading to salmon mortality Visualizing Ecosystem Land Management Assessments (VELMA), an ecohydrological model developed by US Environmental Protection Agency (EPA), was enhanced to better understand and inform stormwater management planning by municipal, state, and federal partners seeking to reduce stormwater contaminant loads in urban streams draining to the Puget Sound National Estuary. This work focuses on the 5.5 km2 Longfellow Creek upper watershed (Seattle, Washington, United States), which has long exhibited high rates of acute urban runoff mortality syndrome in coho salmon. We present VELMA model results to elucidate these processes for the Longfellow Creek watershed across multiple scales-from 5-m grid cells to the entire watershed. Our results highlight hydrological and biogeochemical controls on 6PPD-Q flow paths, and hotspots within the watershed and its stormwater infrastructure, that ultimately impact contaminant transport to Longfellow Creek and Puget Sound. Simulated daily average 6PPD-Q and available observed 6PPD-Q peak in-stream grab sample concentrations (ng/L) corresponds within plus or minus 10 ng/L. Most importantly, VELMA's high-resolution spatial and temporal analysis of 6PPD-Q hotspots provides a tool for prioritizing the locations, amounts, and types of green infrastructure that can most effectively reduce 6PPD-Q stream concentrations to levels protective of coho salmon and other aquatic species.

The effects of intensive trapping on invasive round goby densities.

The round goby (Neogobius melanostomus) is an invasive benthic fish first introduced to the Laurentian Great Lakes in 1990 that has negatively impacted native fishes through increased competition for food and habitat, aggressive interactions, and egg predation. While complete eradication of the round goby is currently not possible, intensive trapping in designated areas during spawning seasons could potentially protect critical native fish spawning habitats. Baited minnow traps were spaced 10 meters apart in shallow water along a 100-meter stretch of shoreline within the Duluth-Superior Harbor during the round goby breeding period (June to October) with captured round gobies removed from interior traps (N = 10) every 48 hours. These traps were bracketed by two pairs of reference traps deployed weekly for 48 hours, from which round gobies were also tagged and released. The number of round gobies captured in the interior traps declined by 67% compared to reference traps over the course of the study, with extended periods of no captures. The tagged round gobies showed high site affinity, with 82.8% of tagged fish recaptured at the previous release site. The results indicate that even at open water sites, which allow natural migration of round gobies into the area, extensive trapping could reduce local population numbers.

Introduction to the special issue on fish bioacoustics: Hearing and sound communicationa).

Fish bioacoustics, or the study of fish hearing, sound production, and acoustic communication, was discussed as early as Aristotle. However, questions about how fishes hear were not really addressed until the early 20th century. Work on fish bioacoustics grew after World War II and considerably in the 21st century since investigators, regulators, and others realized that anthropogenic (human-generated sounds), which had primarily been of interest to workers on marine mammals, was likely to have a major impact on fishes (as well as on aquatic invertebrates). Moreover, passive acoustic monitoring of fishes, recording fish sounds in the field, has blossomed as a noninvasive technique for sampling abundance, distribution, and reproduction of various sonic fishes. The field is vital since fishes and aquatic invertebrates make up a major portion of the protein eaten by a signification portion of humans. To help better understand fish bioacoustics and engage it with issues of anthropogenic sound, this special issue of The Journal of the Acoustical Society of America (JASA) brings together papers that explore the breadth of the topic, from a historical perspective to the latest findings on the impact of anthropogenic sounds on fishes.

3-[18F]Fluoro-para-hydroxyphenethylguanidine (3-[18F]pHPG) PET-A Novel Imaging Modality for Paraganglioma.

Context: Functional positron emission tomography (PET) imaging for the characterization of pheochromocytoma and paraganglioma (PCC/PGL) and for detection of metastases in malignant disease, offers valuable clinical insights that can significantly guide patient treatment. Objective: This work aimed to evaluate a novel PET radiotracer, 3-[18F]fluoro-para-hydroxyphenethylguanidine (3-[18F]pHPG), a norepinephrine analogue, for its ability to localize PCC/PGL. Methods: 3-[18F]pHPG PET/CT whole-body scans were performed on 16 patients (8 male:8 female; mean age 47.6 ± 17.6 years; range, 19-74 years) with pathologically confirmed or clinically diagnosed PCC/PGL. After intravenous administration of 304 to 475 MBq (8.2-12.8 mCi) of 3-[18F]pHPG, whole-body PET scans were performed at 90 minutes in all patients. 3-[18F]pHPG PET was interpreted for abnormal findings consistent with primary tumor or metastasis, and biodistribution in normal organs recorded. Standardized uptake value (SUV) measurements were obtained for target lesions and physiological organ distributions. Results: 3-[18F]pHPG PET showed high radiotracer uptake and trapping in primary tumors, and metastatic tumor lesions that included bone, lymph nodes, and other solid organ sites. Physiological biodistribution was universally present in salivary glands (parotid, submandibular, sublingual), thyroid, heart, liver, adrenals, kidneys, and bladder. Comparison [68Ga]DOTATATE PET/CT was available in 10 patients and in all cases showed concordant distribution. Comparison [123I]meta-iodobenzylguanidine [123I]mIBG planar scintigraphy and SPECT/CT scans were available for 4 patients, with 3-[18F]pHPG showing a greater number of metastatic lesions. Conclusion: We found the kinetic profile of 3-[18F]pHPG PET affords high activity retention within benign and metastatic PCC/PGL. Therefore, 3-[18F]pHPG PET imaging provides a novel modality for functional imaging and staging of malignant paraganglioma with advantages of high lesion affinity, whole-body coregistered computed tomography, and rapid same-day imaging.

Improved purification of cyclotron [68Ga]GaCl3 for the production of 68Ga radiopharmaceuticals.

INTRODUCTION: Increased demand for NetSpot and Illuccix as requirement to receive the respective Lutathera and Pluvicto radiotherapies, and monitor subsequent response to treatment, have reinforced the need to develop alternative ways of producing gallium-68 (68Ga). Building on our efforts to produce 68Ga in a liquid target on a GE PETtrace, the goal of this work is to modify the current GE Gallium Chloride cassette using the FASTLab 2 synthesis module to produce [68Ga]GaCl3 equivalent to a 1.85 GBq generator and demonstrate compatibility with FDA-approved kits for production of 68Ga-labeled radiopharmaceuticals. METHODS: 68Ga was produced in a liquid target via the 68Zn(p,n)68Ga reaction. 68Ga was loaded onto various sizes of ZR resins (ZR Load, 0.3 mL, 1 mL, or 2 mL). The loading efficiency was determined using a dose calibrator. After washing with HNO3, 1.75 M HCl was used to elute the ZR Load resin through various sizes of a second ZR resin (ZR CG, 0 mL, 2 mL, 4 mL). Using 0.5 mL fractions, the elution profile was determined. Compatibility of the [68Ga]GaCl3 with NetSpot and Illuccix kits was investigated. Radiochemical purity (RCP) and 4 h stability were determined using radioTLC and radioHPLC. Using a modified [68Ga]GaCl3 cassette and new FASTLab program, 6 validation preparations were conducted using NetSpot and Illuccix kits for which RCP, stability, sterility and suitability were determined. Dual irradiation of 2 liquid targets was also performed, which was used to simultaneously prepare 1 NetSpot and 2 Illuccix kits by diluting the required activity with 0.1 M HCl. RESULTS: The commercially available GE Cassette gave low RCP using commercial FDA kits. To optimize this, the loading efficiency onto ZR Load and the ratio of ZR resin used to load the initial activity and subsequent elution were explored. When using a 2:4 ratio of ZR Load to ZR CG, 97.89 % RCP was observed when a 3.8 mL [68Ga]GaCl3 solution was used. For Dotatate validation, 0.55 mL of buffer was added to 4.2 mL of [68Ga]GaCl3 which gave 1.35 GBq of formulated product. For Illuccix validation, [68Ga]GaCl3 was added to 2.5 mL of buffer which gave 1.52 GBq of [68Ga]Ga-PSMA-11. Formulated products passed package insert quality control (QC) requirements. When dual target irradiations were performed, 2.84 GBq was delivered to an external vial and used to label 1 NetSpot and 2 Illuccix kits simultaneously, and each kit also met or exceeded established QC criteria. CONCLUSION: Methods are reported for using cyclotron-produced 68Ga from a liquid target in conjunction with FDA-approved NetSpot and Illucix kits. By employing a 2 mL ZR Load resin with a 4 mL ZR CG resin, adequate resolution between residual 68Zn and desired 68Ga was achieved. By modifying the FASTLab procedure to retain the final 2.5 mL of eluate from the ZR CG resin, [68Ga]GaCl3 equivalent to a new 1.85 GBq generator was obtained. This was suitable for labeling NetSpot and Illucix kits, resulting in high incorporation of 68Ga (RCP >95 %), which has not previously been demonstrated. Delivering [68Ga]GaCl3 into an external vial and diluting with 0.1 M HCl makes it possible to prepare multiple kits simultaneously. These new procedures should facilitate use of cyclotron-produced [68Ga]GaCl3 for clinical production going.

Optilume drug-coated balloon for anterior urethral stricture: 2-year results of the ROBUST III trial.

Objective: The aim of this study is to report the updated 2-year results of the intervention arm of the ROBUST III randomized trial evaluating the safety and efficacy of the Optilume drug-coated balloon (DCB) versus standard endoscopic management of recurrent male anterior urethral stricture. Materials and Methods: Eligible patients included men with recurrent anterior urethral stricture ≤3 cm in length and ≤12Fr in diameter, International Prostate Symptom Score (IPSS) ≥11 and peak flow rate (Qmax) <15 mL/s. Patients were randomized to treatment with the Optilume DCB or standard-of-care endoscopic management. Primary efficacy endpoints measured at 2 years included freedom from re-intervention and changes in IPSS, Qmax and post-void residual (PVR). Secondary endpoint was impact on sexual function using the International Index of Erectile Function (IIEF). Primary safety endpoint was freedom from serious procedure- or device-related adverse events (AEs). Results: A total of 127 patients enrolled at 22 sites in the United States and Canada (48 randomized to standard-of-care dilation and 79 to DCB dilation). Seventy-five patients in the DCB arm entered the open-label phase after 6 months. Participants averaged 3.2 prior endoscopic interventions (range 2-10); most (89.9%) had bulbar strictures with an average stricture length of 1.63 cm (SD 0.76). Significant improvements in IPSS, average Qmax and PVR were maintained at 2 years. Freedom from repeat intervention was significantly higher in the Optilume DCB arm at 2 years versus the Control arm at 1 year (77.8% vs. 23.6%, p < 0.001). During the follow-up period, there were 15 treatment failures and two non-study-related deaths. Treatment-related AEs were rare and generally self-limited (haematuria, dysuria and urinary tract infection). Conclusion: The Optilume DCB shows sustained improvement in both objective and subjective voiding parameters at 2-year follow-up. Optilume appears to provide a safe and effective endoscopic treatment alternative for short recurrent anterior urethral strictures among men who wish to avoid or delay formal urethroplasty.

Algorithmic Midline Approach to Perineal Urethrostomy is Associated With Long-term Success and High Patient Satisfaction.

OBJECTIVE: To assess surgical success and patient-reported outcomes of perineal urethrostomy via midline approach. MATERIALS AND METHODS: Charts of patients undergoing primary perineal urethrostomy between May 2008 and June 2022 were reviewed. Background characteristics were assessed; success was defined as freedom from re-intervention. Patient-reported outcome measures were assessed using a cross-sectional phone survey. Several validated questionnaires were used to assess lower urinary tract symptoms, quality of life, and erectile dysfunction. RESULTS: Among 1768 urethroplasties performed over the study period, 103 patients (5.8%) underwent midline perineal urethrostomy. Surgery was successful in 95.1% of cases (98/103); 5 patients (4.9%) required re-intervention at a median of 8.7 months. Post-operative complications occurred in 5.8% of cases (6/103) and were both mild and self-limited. Forty-nine patients (47.6%) were reached via phone survey at a median of 61 months post-operatively. Some questions were not answered by all patients. Most patients (42/49, 86%) were satisfied or very satisfied with surgical results, and 82% (40/49) reported an improvement in their overall health. Most patients (31/41, 76%) were unbothered by sitting to urinate. Although 20% of patients (10/49) reported post-operative urinary symptoms that interfered "a lot" with their daily life, only 3 (6%) of these patients reported dissatisfaction with the outcome. Regarding sexual function, 64% (27/42) reported indifference to or increased satisfaction with sexual encounters vs before surgery. The rate of de novo erectile dysfunction was 24% (12/49). CONCLUSION: The midline approach to perineal urethrostomy provides excellent, durable success rates with high levels of patient satisfaction.

Evaluating immunotherapeutic outcomes in triple-negative breast cancer with a cholesterol radiotracer in mice.

Evaluating the response to immune checkpoint inhibitors (ICIs) remains an unmet challenge in triple-negative breast cancer (TNBC). The requirement for cholesterol in the activation and function of T cells led us to hypothesize that quantifying cellular accumulation of this molecule could distinguish successful from ineffective checkpoint immunotherapy. To analyze accumulation of cholesterol by T cells in the immune microenvironment of breast cancer, we leveraged the PET radiotracer, eFNP-59. eFNP-59 is an analog of cholesterol that our group validated as an imaging biomarker for cholesterol uptake in preclinical models and initial human studies. In immunocompetent mouse models of TNBC, we found that elevated uptake of exogenous labeled cholesterol analogs functions as a marker for T cell activation. When comparing ICI-responsive and -nonresponsive tumors directly, uptake of fluorescent cholesterol and eFNP-59 increased in T cells from ICI-responsive tumors. We discovered that accumulation of cholesterol by T cells increased in ICI-responding tumors that received anti-PD-1 checkpoint immunotherapy. In patients with TNBC, tumors containing cycling T cells had features of cholesterol uptake and trafficking within those populations. These results suggest that uptake of exogenous cholesterol analogs by tumor-infiltrating T cells allows detection of T cell activation and has potential to assess the success of ICI therapy.

So many toadfish, so little timea).

The oyster toadfish, Opsanus tau, has been a valuable biomedical model for a wide diversity of studies. However, its vocalization ability arguably has attracted the most attention, with numerous studies focusing on its ecology, behavior, and neurophysiology in regard to its sound production and reception. This paper reviews 30 years of research in my laboratory using this model to understand how aquatic animals detect, integrate, and respond to external environment cues. The dual vestibular and auditory role of the utricle is examined, and its ability to integrate multimodal input is discussed. Several suggestions for future research are provided, including in situ auditory recording, interjecting natural relevant ambient soundscapes into laboratory sound studies, adding transparency to the field of acoustic deterrents, and calls for fish bioacoustics teaching modules to be incorporated in K-12 curricula to excite and diversify the next generation of scientists.

Evolutionarily related host and microbial pathways regulate fat desaturation in C. elegans.

Fatty acid desaturation is central to metazoan lipid metabolism and provides building blocks of membrane lipids and precursors of diverse signaling molecules. Nutritional conditions and associated microbiota regulate desaturase expression, but the underlying mechanisms have remained unclear. Here, we show that endogenous and microbiota-dependent small molecule signals promote lipid desaturation via the nuclear receptor NHR-49/PPARα in C. elegans. Untargeted metabolomics of a ß-oxidation mutant, acdh-11, in which expression of the stearoyl-CoA desaturase FAT-7/SCD1 is constitutively increased, revealed accumulation of a ß-cyclopropyl fatty acid, becyp#1, that potently activates fat-7 expression via NHR-49. Biosynthesis of becyp#1 is strictly dependent on expression of cyclopropane synthase by associated bacteria, e.g., E. coli. Screening for structurally related endogenous metabolites revealed a ß-methyl fatty acid, bemeth#1, which mimics the activity of microbiota-dependent becyp#1 but is derived from a methyltransferase, fcmt-1, that is conserved across Nematoda and likely originates from bacterial cyclopropane synthase via ancient horizontal gene transfer. Activation of fat-7 expression by these structurally similar metabolites is controlled by distinct mechanisms, as microbiota-dependent becyp#1 is metabolized by a dedicated ß-oxidation pathway, while the endogenous bemeth#1 is metabolized via α-oxidation. Collectively, we demonstrate that evolutionarily related biosynthetic pathways in metazoan host and associated microbiota converge on NHR-49/PPARα to regulate fat desaturation.