The cochlear dose and the age at radiotherapy predict severe hearing loss after passive scattering proton therapy and cisplatin in children with medulloblastoma.

BACKGROUND: Hearing loss (HL) is associated with worse neurocognitive outcomes among patients with medulloblastoma. We aimed to identify risk factors associated with severe HL and to evaluate the generalizability of a published HL calculator among patients treated with passive scattering proton therapy (PSPT) and cisplatin. METHODS: We identified patients aged 3-21 years who were treated at our centers between 2007-2022. Audiograms were graded using the International Society of Pediatric Oncology-Boston scale. Time to grade 3-4 HL was evaluated using Kaplan-Meier and multivariable Cox models to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Seventy-nine patients were treated with PSPT at a median age of 7.5 years (range:3.1-21.1). The mean cochlear dose (Dmc) (±S.D.) was 31.5±8.5 Gy, and the cumulative cisplatin dose was 295±50 mg/m2. Fifty-nine patients (75%) received amifostine. Patients completed a median of 9 audiograms (range:4-22) with a median audiogram follow-up of 49 months (range:6-177). Twenty-seven patients (34%) had grade 3-4 HL. In adjusted Cox models, only higher Dmc (HR=1.12, 95% CI:1.06-1.18) was associated with grade 3-4 HL. The predicted 3-year incidence of grade 3-4 HL was 40.0% (95% CI: 21.3-66.3) and 66.7% (95% CI: 35.4-93.7) for children with Dmc ≥36 Gy and age at radiotherapy ≥7 and <7 years, respectively (p=0.042). It was 8.9% (95% CI: 2.3-31.6) and 15.6% (95% CI: 5.3-41.1) for children with Dmc <36 Gy and age at radiotherapy ≥7 and <7 years, respectively (p=0.78). CONCLUSIONS: Children <7 years at radiotherapy with a Dmc ≥36 Gy are at higher risk for HL.

The Role of CCL Chemokines in Experimental Staphylococcus aureus Endophthalmitis.

Purpose: To test the hypothesis that (C-C motif) ligand 2 (CCL2) and CCL3 impact retinal function decline and inflammation during Staphylococcus aureus endophthalmitis. Methods: Experimental endophthalmitis was initiated by intravitreal injection of 5000 colony-forming units of S. aureus into the eyes of C57BL/6J, CCL2-/-, or CCL3-/- mice. At 12 and 24 hours post-infection, retinal function, bacterial load, and myeloperoxidase levels were quantified. Results: During S. aureus endophthalmitis, we observed a significant improvement in retinal function in CCL2-/- mice relative to C57BL/6J mice at 12 hours but not at 24 hours. In CCL3-/- mice, retinal function was significantly improved relative to C57BL/6J mice at 12 and 24 hours. The absence of CCL2 did not alter intraocular S. aureus intraocular concentrations. However, CCL3-/- mice had significantly lower intraocular S. aureus at 12 hours but not at 24 hours. No difference in myeloperoxidase levels was observed between C57BL/6J and CCL2-/- mice at 12 hours. CCL3-/- mice had almost no myeloperoxidase at 12 hours. At 24 hours, increased myeloperoxidase was observed in CCL2-/- and CCL3-/- mice relative to C57BL/6J mice. Conclusions: Although the absence of CCL2 resulted in improved retinal function retention at 12 hours, CCL3 deficiency resulted in improved retinal function at 12 and 24 hours. CCL3 deficiency, but not CCL2 deficiency, resulted in almost no inflammation at 12 hours. However, at 24 hours, the absence of CCL2 or CCL3 resulted in significantly increased inflammation. These results suggest that, although both CCL2 and CCL3 impact intraocular infection outcomes, CCL3 may have a more significant impact in S. aureus endophthalmitis.

Evolution and engineering of pathways for aromatic O-demethylation in Pseudomonas putida KT2440.

Biological conversion of lignin from biomass offers a promising strategy for sustainable production of fuels and chemicals. However, aromatic compounds derived from lignin commonly contain methoxy groups, and O-demethylation of these substrates is often a rate-limiting reaction that influences catabolic efficiency. Several enzyme families catalyze aromatic O-demethylation, but they are rarely compared in vivo to determine an optimal biocatalytic strategy. Here, two pathways for aromatic O-demethylation were compared in Pseudomonas putida KT2440. The native Rieske non-heme iron monooxygenase (VanAB) and, separately, a heterologous tetrahydrofolate-dependent demethylase (LigM) were constitutively expressed in P. putida, and the strains were optimized via adaptive laboratory evolution (ALE) with vanillate as a model substrate. All evolved strains displayed improved growth phenotypes, with the evolved strains harboring the native VanAB pathway exhibiting growth rates ∼1.8x faster than those harboring the heterologous LigM pathway. Enzyme kinetics and transcriptomics studies investigated the contribution of selected mutations toward enhanced utilization of vanillate. The VanAB-overexpressing strains contained the most impactful mutations, including those in VanB, the reductase for vanillate O-demethylase, PP_3494, a global regulator of vanillate catabolism, and fghA, involved in formaldehyde detoxification. These three mutations were combined into a single strain, which exhibited approximately 5x faster vanillate consumption than the wild-type strain in the first 8 h of cultivation. Overall, this study illuminates the details of vanillate catabolism in the context of two distinct enzymatic mechanisms, yielding a platform strain for efficient O-demethylation of lignin-related aromatic compounds to value-added products.

Beyond the MUN domain, Munc13 controls priming and depriming of synaptic vesicles.

Synaptic vesicle docking and priming are dynamic processes. At the molecular level, SNAREs (soluble NSF attachment protein receptors), synaptotagmins, and other factors are critical for Ca2+-triggered vesicle exocytosis, while disassembly factors, including NSF (N-ethylmaleimide-sensitive factor) and α-SNAP (soluble NSF attachment protein), disassemble and recycle SNAREs and antagonize fusion under some conditions. Here, we introduce a hybrid fusion assay that uses synaptic vesicles isolated from mouse brains and synthetic plasma membrane mimics. We included Munc18, Munc13, complexin, NSF, α-SNAP, and an ATP-regeneration system and maintained them continuously-as in the neuron-to investigate how these opposing processes yield fusogenic synaptic vesicles. In this setting, synaptic vesicle association is reversible, and the ATP-regeneration system produces the most synchronous Ca2+-triggered fusion, suggesting that disassembly factors perform quality control at the early stages of synaptic vesicle association to establish a highly fusogenic state. We uncovered a functional role for Munc13 ancillary to the MUN domain that alleviates an α-SNAP-dependent inhibition of Ca2+-triggered fusion.

Delayed Sternal Closure vs Emergency Sternal Reopening in Adults With Congenital Heart Disease.

BACKGROUND: Limited data exist regarding outcomes of delayed sternal closure (DSC) in adults with congenital heart disease (ACHD). METHODS: We reviewed 159 ACHD patients undergoing cardiac operation from 1993 to 2023 who required DSC (open sternum at the end of operation, n = 112) or sternum emergently reopened (n = 47). Regression models were performed to determine factors associated with outcomes. RESULTS: Of 112 patients undergoing DSC, 87 patients (77.6%) underwent DSC ≤4 days and 25 patients (22.3%) >4 days. The most common operations were valve (n = 35 [31.2%]), aortic (n = 33 [29.4%]), and right ventricular outflow tract procedures (n = 23 [20.5%]). Median time to chest closure was 2 days (interquartile range, 1-5 days). Apart from sex, baseline characteristics were similar between DSC groups. A stepwise increase in early mortality was observed from DSC ≤4 days to DSC >4 days (6.8% vs 32%), as well as the incidence of early complications, except sternal infection. Risk factors associated with early mortality were age (P = .02), DSC >4 days (P < .001), hemodynamic indication (P = .03), and single ventricle (P = .02). On multivariable analysis, lower ejection fraction (P = .04), hemodynamic indication (P = .02), single ventricle (P = .004), and diabetes mellitus (P = .03) were predictors of prolonged time to chest closure. Among hospital survivors, late survival was similar between patients undergoing DSC ≤4 days vs >4 days (P = .48). CONCLUSIONS: A brief duration of DSC in ACHD patients is associated with low morbidity and mortality. Higher early mortality and complications were observed among patients who did not achieve chest closure within 4 days.

Mentorship for Transfer Student Success in STEM Research: Mentor Approaches and Reflections.

Mentorship has been widely recognized as an effective means to promote student learning and engagement in undergraduate research experiences. However, little work exists for understanding different mentors' perceived approaches to mentorship, including mentorship of students from backgrounds and educational trajectories not well represented in science, technology, engineering, and mathematics (STEM). Transfer students, in particular, face unique trajectories in their pursuit of research opportunities, yet few studies investigate how mentors describe their approaches to supporting these students. Using semistructured interviews, this study examines how mentors approach mentoring students from diverse backgrounds as research trainees, with an emphasis on transfer students. First, using phenomenography as an analytical approach, we identified four categories describing variations in how mentors reflected upon or accounted for the transfer student identity in their approaches. We find that research mentors vary in their understanding and exposure to the transfer student identity and may have preconceived notions of the transfer student experience. Second, we present vignettes to illustrate how mentors' approaches to the transfer student identity may relate or diverge from their general approaches to mentoring students from different backgrounds and identities. The emerging findings have implications for developing effective mentorship strategies and training mentors to support transfer students.

Associations Between Traumatic Brain Injury and Severity of Tinnitus-Related Functional Impairment Among US Military Veterans: A National, Population-Based Study.

OBJECTIVE: To describe associations between a history of traumatic brain injury (TBI) and the severity of tinnitus-related functional impairment among a national, stratified random sample of veterans diagnosed with tinnitus by the Department of Veterans Affairs (VA) healthcare system. SETTING: A multimodal (mailed and internet) survey administered in 2018. Participants: VA healthcare-using veterans diagnosed with tinnitus; veterans with comorbid TBI diagnosis were oversampled. DESIGN: A population-based survey. MAIN MEASURES: TBI history was assessed using International Classification of Diseases (ICD) diagnosis codes in veterans' VA electronic health records. The severity of participants' overall tinnitus-related functional impairment was measured using the Tinnitus Functional Index. Population prevalence and 95% confidence intervals (CIs) were estimated using inverse probability weights accounting for sample stratification and survey nonresponse. Veterans' relative risk ratios of very severe or moderate/severe tinnitus-related functional impairment, versus none/mild impairment, were estimated by TBI history using bivariable and multivariable multinomial logistic regression. RESULTS: The population prevalence of TBI was 5.6% (95% CI: 4.8-6.4) among veterans diagnosed with tinnitus. Veterans with a TBI diagnosis, compared with those without a TBI diagnosis, had 3.6 times greater likelihood of rating their tinnitus-related impairment as very severe (95% CI: 2.1-6.3), and 1.5 times greater likelihood of rating their impairment as moderate/severe (95% CI: 1.0-2.4), versus none/mild. CONCLUSIONS: These findings suggest an important role of TBI in the severity of tinnitus-related functional impairment among veterans. This knowledge can help inform the integration of tinnitus management services into the care received by veterans with TBI.

Reporting of Complications in Rhinoplasty Randomized Controlled Trials: An Analysis Using the CONSORT Extension for Harms Checklist.

OBJECTIVE: This study aimed to assess the completeness of adverse event (AE) reporting in randomized control trials (RCTs) focused on rhinoplasty, using the Consolidated Standards for Reporting (CONSORT) Extension for Harms checklist. STUDY DESIGN: A cross-sectional design was employed to review RCTs related to rhinoplasty published between January 1, 2005, and January 28, 2022. SETTING: The study analyzed clinical trials on rhinoplasty retrieved from PubMed. METHODS: We performed a comprehension search on PubMed, blind and duplicate screening, and data extraction. Adherence to the 18 recommendations of the CONSORT Extension for Harms was evaluated, with 1 point assigned for each adhered item. Percent adherence was calculated based on the 18 points, taking into account the multiple subcategories within some recommendations. Descriptive statistics were used to summarize adherence-including frequencies, percentages, and 95% confidence intervals. RESULTS: Our search returned 240 articles, of which 56 met inclusion criteria. No RCTs adhered to all 18 CONSORT Extension for Harms items. Twenty-six (26/56, 46.4%) adhered to ≥50% of the items, and 30 (30/56, 53.6%) adhered to ≥33.3% of the items. Seven (7/56, 12.5%) RCTs adhered to no items. Across all RCTs, the average number of CONSORT-Harms items adhered to was 7.2 (7.2/18, 40.0%). The most adhered to item was item 10. Discussion balanced with regard to efficacy and AEs (80.4%, [70.0-90.8]). CONCLUSION: This study highlights the inadequacy of AE reporting in rhinoplasty RCTs according to CONSORT-Harms guidelines. Urgent efforts are required to bridge this reporting gap and enhance transparency in surgical research, ultimately safeguarding patient well-being.

Current advances in serological and molecular diagnosis of Schistosoma mekongi infection.

Schistosomiasis, a neglected tropical disease, caused by blood flukes belonging to the genus Schistosoma; it persists as a public health problem in selected regions throughout Africa, South America, and Asia. Schistosoma mekongi, a zoonotic schistosome species endemic to the Mekong River in Laos and Cambodia, is one of the significant causes of human schistosomiasis along with S. japonicum, S. mansoni, S. haematobium and S. intercalatum. Since its discovery, S. mekongi infection has been highly prevalent in communities along the Mekong River. Although surveillance and control measures have shown success in recent years, more robust diagnostic tools are still needed to establish more efficient control and prevention strategies to achieve and sustain an elimination status. Diagnosis of S. mekongi infection still relies on copro-parasitological techniques, commonly made by Kato-Katz stool examination. Serological techniques such as enzyme-linked immunosorbent assay (ELISA) may also be applicable but in a limited setting. Targeted molecular and serological tools specific to the species, on the other hand, have been limited. This is due, in part, to the limited research and studies on the molecular biology of S. mekongi since genome information of this species has not yet been released. In this review, current advances, and gaps and limitations in the molecular and immunological diagnosis of S. mekongi are discussed.

A Mixed-Methods Exploration of Competencies and Professional Development Needs Among Chief Certified Registered Nurse Anesthetists.

This project sought to explore the experiences, self-perceived preparation, professional development needs, and preferred learning methods of certified registered nurse anesthetists (CRNAs) in a management role. A sample of 10 current chief CRNAs responded to a demographics survey and participated in one-on-one interviews using a 14-question, semi-structured interview framework modified from a previous study. Interview responses were deidentified and qualitatively analyzed for common themes by two content experts and one qualitative analysis expert. Results suggest that CRNAs entering the management field feel somewhat unprepared to perform the administrative tasks associated with their role. Qualitative analysis of interview responses elicited multiple key themes including interpersonal communication and handling crucial conversations, time and organizational management skills, team building and motivation, and financial management skills. Themes related to preferred learning methods of chief CRNAs included mentorship, peer networking, and experiential learning to obtain the required knowledge and skills for the role. The authors recommend incorporating each of the identified themes to guide development of CRNA management-specific educational programs. Establishing such a program will serve to better prepare aspiring CRNA managers and further develop the knowledge and skillset of current chief CRNAs.

Ultrabroadband Near-Infrared Transient Absorption Spectrometer with Simultaneous 900-2350†nm Detection.

In this work, we detail an ultrafast pump-probe transient absorption (TA) spectrometer capable of probing the near-infrared (NIR) spectral region from 900 to 2350 nm simultaneously. Two key advances were required to overcome previous spectral window limitations, which typically result from constrained supercontinuum ranges (e.g., 1700 nm) and/or InGaAs detector line rates, especially those with >1700 nm range. First, we generated a broadband NIR supercontinuum using the 1980 nm idler beam of an optical parametric amplifier and implement a unique spectral filtering scheme to balance the detected spectrum. Second, we used a prism-based spectrometer system equipped with high speed InGaAs cameras having ∼2500 nm sensitivity cutoffs. To the best knowledge of the authors, such an extended probe range was previously inaccessible because the combination of two optical geometries either using different supercontinuum crystal materials for generating the NIR and shortwave infrared (SWIR) regions, or using differing pump wavelengths, were required. Finally, we demonstrate the performance and capabilities of the ultrabroadband TA spectroscopy system by presenting data showing ultrafast charge photogeneration in a polymer : fullerene blend thin-film and comparing the results to the literature with a complete agreement.

A model for delivery of extracorporeal life support in a stand-alone veterans affairs medical center.

INTRODUCTION: For the Veterans Health Administration (VHA) to continue to perform complex cardiothoracic surgery, there must be an established pathway for providing urgent/emergent extracorporeal life support (ECLS). Partnership with a nearby tertiary care center with such expertise may be the most resource-efficient way to provide ECLS services to patients in post-cardiotomy cardiogenic shock or respiratory failure. The goal of this project was to assess the efficiency, safety, and outcomes of surgical patients who required transfer for perioperative ECLS from a single stand-alone Veterans Affairs Medical Center (VAMC) to a separate ECLS center. METHODS: Cohort consisted of all cardiothoracic surgery patients who experienced cardiogenic shock or refractory respiratory failure at the local VAMC requiring urgent or emergent institution of ECLS between 2019 and 2022. The primary outcomes are the safety and timeliness of transport. RESULTS: Mean time from the initial shock call to arrival at the ECLS center was 2.8 h. There were no complications during transfer. Six patients (86%) survived to decannulation. CONCLUSION: These results suggest that complex cardiothoracic surgery can be performed within the VHA system and when there is an indication for ECLS, those services can be safely and effectively provided at an affiliated, properly equipped center.

Mechanism-Guided Kinetic Analysis of Electrocatalytic Proton Reduction Mediated by a Cobalt Catalyst Bearing a Pendant Basic Site.

Cobalt polypyridyl complexes stand out as efficient catalysts for electrochemical proton reduction, but investigations into their operating mechanisms, with broad-reaching implications in catalyst design, have been limited. Herein, we investigate the catalytic activity of a cobalt(II) polypyridyl complex bearing a pendant pyridyl base with a series of organic acids spanning 20 pKa units in acetonitrile. Structural analysis, as well as electrochemical studies, reveals that the Co(III) hydride intermediate is formed through reduction of the Co(II) catalyst followed by direct metal protonation in the initial EC step despite the presence of the pendant base, which is commonly thought of as a more kinetically accessible protonation site. Protonation of the pendant base occurs after the Co(III) hydride intermediate is further reduced in the overall ECEC pathway. Additionally, when the acid used is sufficiently strong, the Co(II) catalyst can be protonated, and the Co(III) hydride can react directly with acid to release H2. With thorough mechanistic understanding, the appropriate electroanalytical methods were identified to extract rate constants for the elementary steps over a range of conditions. Thermodynamic square schemes relating catalytic intermediates proposed in the three electrocatalytic HER mechanisms were constructed. These findings reveal a full description of the HER electrocatalysis mediated by this molecular system and provide insights into strategies to improve synthetic fuel-forming catalysts operative through metal hydride intermediates.

Microfluidics enabled multi-omics triple-shot mass spectrometry for cell-based therapies.

In recent years, cell-based therapies have transformed medical treatment. These therapies present a multitude of challenges associated with identifying the mechanism of action, developing accurate safety and potency assays, and achieving low-cost product manufacturing at scale. The complexity of the problem can be attributed to the intricate composition of the therapeutic products: living cells with complex biochemical compositions. Identifying and measuring critical quality attributes (CQAs) that impact therapy success is crucial for both the therapy development and its manufacturing. Unfortunately, current analytical methods and tools for identifying and measuring CQAs are limited in both scope and speed. This Perspective explores the potential for microfluidic-enabled mass spectrometry (MS) systems to comprehensively characterize CQAs for cell-based therapies, focusing on secretome, intracellular metabolome, and surfaceome biomarkers. Powerful microfluidic sampling and processing platforms have been recently presented for the secretome and intracellular metabolome, which could be implemented with MS for fast, locally sampled screening of the cell culture. However, surfaceome analysis remains limited by the lack of rapid isolation and enrichment methods. Developing innovative microfluidic approaches for surface marker analysis and integrating them with secretome and metabolome measurements using a common analytical platform hold the promise of enhancing our understanding of CQAs across all "omes," potentially revolutionizing cell-based therapy development and manufacturing for improved efficacy and patient accessibility.

Data-Sharing Across Otolaryngology: Comparing Journal Policies and Their Adherence to the FAIR Principles.

OBJECTIVE: Data-sharing plays an essential role in advancing scientific understanding. Here, we aim to identify the commonalities and differences in data-sharing policies endorsed by otolaryngology journals and to assess their adherence to the FAIR (findable, accessible, interoperable, reusable) principles. METHODS: Data-sharing policies were searched for among 111 otolaryngology journals, as listed by Scimago Journal & Country Rank. Policy extraction of the top biomedical journals as ranked by Google Scholar metrics were used as a comparison. The FAIR principles for scientific data management and stewardship were used for the extraction framework. This occurred in a blind, masked, and independent fashion. RESULTS: Of the 111 ranked otolaryngology journals, 100 met inclusion criteria. Of those 100 journals, 79 provided data-sharing policies. There was a clear lack of standardization across policies, along with specific gaps in accessibility and reusability which need to be addressed. Seventy-two policies (of 79; 91%) designated that metadata should have globally unique and persistent identifiers. Seventy-one (of 79; 90%) policies specified that metadata should clearly include the identifier of the data they describe. Fifty-six policies (of 79; 71%) outlined that metadata should be richly described with a plurality of accurate and relevant attributes. CONCLUSION: Otolaryngology journals have varying data-sharing policies, and adherence to the FAIR principles appears to be moderate. This calls for increased data transparency, allowing for results to be reproduced, confirmed, and debated.

Expression profile analysis of the transient receptor potential (TRPM) channel, a possible target of praziquantel in Schistosoma japonicum.

The WHO considers schistosomiasis, which is controlled by the mass administration of the drug praziquantel (PZQ), to be a neglected tropical disease. Despite its clinical use for over four decades, PZQ remains the only choice of chemotherapy against this disease. Regarding the previous studies that demonstrated that PZQ activates the transient receptor potential (TRP) channel in Schistosoma mansoni (Sm.TRPMPZQ), the expression profile of the ortholog of this channel gene (Smp_246790.5) in S. japonicum (EWB00_008853) (Sj.TRPMPZQ) was analyzed. The relative expression of this gene in various stages of the parasite lifecycle was analyzed by quantitative real-time reverse transcription-PCR (qRT-PCR), and the expression of Sj.TRPMPZQ was observed by immunohistochemical staining using anti-serum against the recombinant Sj.TRPMPZQ protein. qRT-PCR revealed the significantly lower mRNA expression in the snail stage in comparison to other stages (p < 0.01). The relative quantity of the Sj.TRPMPZQ expression for paired females, unpaired males, and eggs was 60%, 56%, and 68%, respectively, in comparison to paired males that showed the highest expression (p < 0.05). Interestingly, immunostaining demonstrated that Sj.TRPMPZQ is expressed in the parenchyma which contains muscle cells, neuronal cells and tegument cells in adult worms. This may support the two major effects of PZQ-worm paralysis and tegument disruption-induced by channel activation. Moreover, the channel was expressed in both the eggshell and the miracidia inside, but could not be observed in sporocyst. These results suggest that the expression of Sj.TRPMPQZ corresponds to the known sensitivity of S. japonicum to PZQ.

High-Performance Wearable Organic Photodetectors by Molecular Design and Green Solvent Processing for Pulse Oximetry and Photoplethysmography.

White-light detection from the visible to the near-infrared region is central to many applications such as high-speed cameras, autonomous vehicles, and wearable electronics. While organic photodetectors (OPDs) are being developed for such applications, several challenges must be overcome to produce scalable high-detectivity OPDs. This includes issues associated with low responsivity, narrow absorption range, and environmentally friendly device fabrication. Here, an OPD system processed from 2-methyltetrahydrofuran (2-MeTHF) sets a record in light detectivity, which is also comparable with commercially available silicon-based photodiodes is reported. The newly designed OPD is employed in wearable devices to monitor heart rate and blood oxygen saturation using a flexible OPD-based finger pulse oximeter. In achieving this, a framework for a detailed understanding of the structure-processing-property relationship in these OPDs is also developed. The bulk heterojunction (BHJ) thin films processed from 2-MeTHF are characterized at different length scales with advanced techniques. The BHJ morphology exhibits optimal intermixing and phase separation of donor and acceptor moieties, which facilitates the charge generation and collection process. Benefitting from high charge carrier mobilities and a low shunt leakage current, the newly developed OPD exhibits a specific detectivity of above 1012  Jones over 400-900 nm, which is higher than those of reference devices processed from chlorobenzene and ortho-xylene.

The progranulin cleavage product granulin 3 exerts a dominant negative effect on animal fitness.

Progranulin is an evolutionarily conserved protein that has been implicated in human neurodevelopmental and neurodegenerative diseases. Human progranulin is comprised of multiple cysteine-rich, biologically active granulin peptides. Granulin peptides accumulate with age and stress, however their functional contributions relative to full-length progranulin remain unclear. To address this, we generated C. elegans strains that produced quantifiable levels of both full-length progranulin/PGRN-1 protein and cleaved granulin peptide. Using these strains, we demonstrated that even in the presence of intact PGRN-1, granulin peptides suppressed the activity of the lysosomal aspartyl protease activity, ASP-3/CTSD. Granulin peptides were also dominant over PGRN-1 in compromising animal fitness as measured by progress through development and stress response. Finally, the degradation of human TDP-43 was impaired when the granulin to PGRN-1 ratio was increased, representing a disease-relevant downstream impact of impaired lysosomal function. In summary, these studies suggest that not only absolute progranulin levels, but also the balance between full-length progranulin and its cleavage products, is important in regulating lysosomal biology. Given its relevance in human disease, this suggests that the processing of progranulin into granulins should be considered as part of disease pathobiology and may represent a site of therapeutic intervention.

Factors Predicting Apparent Ophidiomycosis in Wild Brown Watersnakes (Nerodia taxispilota).

Ophidiomycosis, also known as snake fungal disease, is caused by Ophidiomyces ophidiicola and is a threat to snake conservation worldwide. Ophidiomycosis has been reported throughout much of the eastern US, and outbreaks have been associated with local population declines of already strained populations. Previous studies report significant variability in ophidiomycosis among species sampled, with higher prevalence typically observed in Nerodia spp. Although ophidiomycosis can lead to morbidity and mortality in affected individuals, little is known about disease dynamics in free-ranging populations. Herein, we examine how individual-specific factors (e.g., life stage [immature, mature], contaminant status, sex, hemograms) may be associated with ophidiomycosis status in the brown watersnake (Nerodia taxispilota). During 2018-19, we sampled 97 N. taxispilota from five locations along the Savannah River in South Carolina and Georgia, US. Ophidiomyces ophidiicola DNA was detected in 66 snakes for a prevalence of 68% (95% confidence interval, 59-77). Mature snakes had a significantly higher risk of apparent ophidiomycosis (skin lesions present and quantitative PCR [qPCR], positive) relative to immature snakes. Snakes classified as having possible (skin lesions present, but qPCR negative) or apparent ophidiomycosis exhibited a relative azurophilia and heterophilia compared with individuals classified as negative (P≤0.037). Nerodia taxispilota in this region appear to have a high prevalence of apparent ophidiomycosis (22%; 95% CI, 14-31), similar to previous reports from the southeastern US. Additional epidemiologic investigations are warranted to further elucidate other individual-specific and environmental factors that may dictate disease risk and outcomes in affected populations.

Comparison of a Valveless Trocar System and Conventional Insufflation in Pediatric Urologic Surgery.

Background: Conventional operative insufflation uses a one-way trocar to handle instruments while maintaining pneumoperitoneum. In 2007, the AirSeal® valveless trocar insufflation system was introduced, which maintains stable pneumoperitoneum while continuously evacuating smoke. Although this device has been validated in adult patients, it has not been extensively validated in the pediatric population. Materials and Methods: A retrospective cohort study of pediatric urology patients aged 0 to 21 who underwent laparoscopic pyeloplasty between March 2016 and October 2021 was performed. Intraoperative physiologic parameters, procedure characteristics, postoperative outcomes, and demographics of each patient in whom either AirSeal insufflation system (AIS) or conventional insufflation system (CIS) was utilized were obtained from hospital records. Data were compared across the AIS and CIS cohorts. The primary outcomes were intraoperative anesthetic and physiologic parameters, including end tidal carbon dioxide, oxygen saturation, body temperature, positive inspiratory pressure, systolic blood pressure, and heart rate. Results: There were no significant differences in the anesthetic and physiologic parameters in the AIS and CIS groups. In addition, no differences in demographics, procedural characteristics, or complication rates were found between the cohorts. Conclusion: The AirSeal valveless trocar insufflation system demonstrates comparable intraoperative anesthetic and physiologic outcomes compared to conventional one-way valve insufflation in pediatric laparoscopic pyeloplasty. Certain surgeon-related qualitative metrics are underappreciated in this study, however, including improved visualization with vigorous suctioning and pressure maintenance with frequent instrument exchanges. Surgeon experience may mask the benefits of these characteristics as it pertains to quantitative surgical outcomes such as estimated blood loss, operative time, and perioperative complications.