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Extradural neoplasms are the most common spinal tumors in small animals. A bilobed appearance of ventral extradural spinal lesions ("gullwing sign") on MRI has been described with various conditions. The objective of this retrospective study was to determine if a "gullwing sign" is more common with certain types of extradural tumors. MRI studies of dogs and cats with extradural spinal neoplasms were reviewed for the presence of a "gullwing sign". Statistical analysis was performed to evaluate a possible relationship between tumor class and the presence of a "gullwing sign". Sixty-six cases were included (5 epithelial, 31 mesenchymal, 4 neuroendocrine, and 26 round cell tumors). A "gullwing sign" was identified in 12 of 66 cases (18.2%) and was significantly more common with round cell neoplasia than other tumor types (P < .001; OR = 28.6, 95% CI [3.4, 241.1]). This information may aid radiologists in prioritizing differential diagnoses for extradural tumors in small animals., (© 2024 American College of Veterinary Radiology.)

Base editing could correct nonsense mutations that cause cystic fibrosis (CF), but clinical development is limited by the lack of delivery methods that efficiently breach the barriers presented by airway epithelia. Here, we present a novel amphiphilic shuttle peptide based on the previously reported S10 peptide that substantially improved base editor ribonucleoprotein (RNP) delivery. Studies of the S10 secondary structure revealed that the alpha-helix formed by the endosomal leakage domain (ELD), but not the cell penetrating peptide (CPP), was functionally important for delivery. By isolating and extending the ELD, we created a novel shuttle peptide, termed S237. While S237 achieved lower delivery of green fluorescent protein, it outperformed S10 at Cas9 RNP delivery to cultured human airway epithelial cells and to pig airway epithelia in vivo, possibly due to its lower net charge. In well-differentiated primary human airway epithelial cell cultures, S237 achieved a 4.6-fold increase in base editor RNP delivery, correcting up to 9.4% of the cystic fibrosis transmembrane conductance regulator (CFTR) R553X allele and restoring CFTR channel function close to non-CF levels. These findings deepen the understanding of peptide-mediated delivery and offer a translational approach for base editor RNP delivery for CF airway disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Abstract: Tremblay, M, Anderson Sirois, S, Verville, W, Auger, M, Abboud, J, and Descarreaux, M. Acute upper-body and lower-body neuromuscular fatigue effect on baseball pitchers' velocity: A pilot study. J Strength Cond Res 38(8): 1447-1452, 2024-The purpose of this pilot study was to explore the acute effect of upper-body and lower-body neuromuscular fatigue protocols on baseball pitchers' velocity. Sixteen baseball pitchers were recruited, and a crossover design was used to meet the study purpose. Pitchers were tested twice, 7 days apart, with their upper-body and lower-body explosiveness, pitching velocity, and muscle soreness perception of their throwing arm (forearm flexors, biceps, anterior deltoid, and upper trapezius muscles) assessed before and after an upper-body and lower-body neuromuscular fatigue protocol. Two-way analysis of variances and paired t tests ( p < 0.05) were used to identify and compare prescores and postscores. Following both fatigue protocols, results revealed a significant decrease in time for pitching velocity ( p = 0.005, ηp 2 = 0.462), and increases in muscle soreness perception of the forearm flexors ( p = 0.005, ηp 2 = 0.470), anterior deltoid ( p = 0.045, ηp 2 = 0.274), and upper trapezius ( p = 0.023, ηp 2 = 0.339) muscles. Paired t test results showed a significant decrease in preneuromuscular and postneuromuscular fatigue protocol in the upper-body ( p < 0.01) and lower-body ( p < 0.01) explosiveness scores. These pilot study results show the impact of different exercise protocols on pitchers' explosiveness, velocity, and muscle soreness perception emphasizing the need for further investigation into the acute effect of exercise targeting the upper or lower-body on pitching performance, specifically at the pitcher's position., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the National Strength and Conditioning Association.)

Delivery of antisense oligonucleotides (ASOs) to airway epithelial cells is arduous due to the physiological barriers that protect the lungs and the endosomal entrapment phenomenon, which prevents ASOs from reaching their intracellular targets. Various delivery strategies involving peptide-, lipid-, and polymer-based carriers are being investigated, yet the challenge remains. S10 is a peptide-based delivery agent that enables the intracellular delivery of biomolecules such as GFP, CRISPR-associated nuclease ribonucleoprotein (RNP), base editor RNP, and a fluorescent peptide into lung cells after intranasal or intratracheal administrations to mice, ferrets, and rhesus monkeys. Herein, we demonstrate that covalently attaching S10 to a fluorescently labeled peptide or a functional splice-switching phosphorodiamidate morpholino oligomer improves their intracellular delivery to airway epithelia in mice after a single intranasal instillation. Data reveal a homogeneous delivery from the trachea to the distal region of the lungs, specifically into the cells lining the airway. Quantitative measurements further highlight that conjugation via a disulfide bond through a pegylated (PEG) linker was the most beneficial strategy compared with direct conjugation (without the PEG linker) or conjugation via a permanent thiol-maleimide bond. We believe that S10-based conjugation provides a great strategy to achieve intracellular delivery of peptides and ASOs with therapeutic properties in lungs., Competing Interests: D.G. holds equity in Feldan Therapeutics. N.B., M.A., L.S.M., I.A., L.F.G., X.C., M.H., D.G., and A.H.S. are employees of Feldan Therapeutics. A.H.S. and D.G. have filed patent applications. A.H.S. and D.G. are inventors of a patent related to peptide bioconjugates as delivery agent, and D.G. is also inventor of patents related to peptide-based delivery agents, which are assigned to Feldan Bio Inc., (© 2024 The Author(s).)

Introduction: Hypoglycemia is a common symptom in pediatrics that can lead to neurological sequelae. The etiologies are mostly benign, but hypoglycemia can be a symptom of severe underlying disease. To streamline the etiological investigations, a "hypoglycemia kit," containing supplies needed to perform specific analyses quickly, was made available in the pediatric emergency department of the Rouen University Hospital in 2011. Since its introduction, this kit has been used to explore all cases of hypoglycemia regardless of the context. However, although very useful, these analyses are expensive. The objective of our study was to examine the cost-effectiveness of this kit and to refine its indications if necessary., Methods: This was a non-interventional and retrospective single-center study. Digital records of patients for whom a hypoglycemia kit was used from September 2011 to August 2019 at the pediatric emergency department of Rouen University Hospital were used to retrieve clinical characteristics, laboratory results, and the causes of hypoglycemia., Results: The study included 82 patients. The etiologic investigation concluded that 74 patients had functional hypoglycemia, and eight cases were attributed to other etiologies. In two cases, the kit led to a diagnosis, i.e., 2.4 % efficiency. A history of congenital malformations or previous hypoglycemia was significantly associated with severe etiologies. However, there was no significant association between hypoglycemia severity, age, sex, and these etiologies., Conclusion: Our study reveals that the cost-effectiveness of the hypoglycemia kit is low in pediatric emergencies (2.4 %) at Rouen University Hospital, where functional hypoglycemia remains the leading cause of hypoglycemia. However, our results allow us to suggest a decision tree for refining the usability of this kit, which would considerably increase its efficiency., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

The cell membrane is a restrictive biological barrier, especially for large, charged molecules, such as proteins. The use of cell-penetrating peptides (CPPs) can facilitate the delivery of proteins, protein complexes, and peptides across the membrane by a variety of mechanisms that are all limited by endosomal sequestration. To improve CPP-mediated delivery, we previously reported the rapid and effective cytosolic delivery of proteins in vitro and in vivo by their coadministration with the peptide S10, which combines a CPP and an endosomal leakage domain. Amphiphilic peptides with hydrophobic properties, such as S10, can interact with lipids to destabilize the cell membrane, thus promoting cargo internalization or escape from endosomal entrapment. However, acute membrane destabilization can result in a dose-limiting cytotoxicity. In this context, the partial or transient deactivation of S10 by modification with methoxy poly(ethylene glycol) (mPEG; i.e., PEGylation) may provide the means to alter membrane destabilization kinetics, thereby attenuating the impact of acute permeabilization on cell viability. This study investigates the influence of PEGylation parameters (molecular weight, architecture, and conjugation chemistry) on the delivery efficiency of a green fluorescent protein tagged with a nuclear localization signal (GFP-NLS) and cytotoxicity on cells in vitro. Results suggest that PEGylation mostly interferes with adsorption and secondary structure formation of S10 at the cell membrane, and this effect is exacerbated by the mPEG molecular weight. This effect can be compensated for by increasing the concentration of conjugates prepared with lower molecular weight mPEG (5 to ∼20 kDa) but not for conjugates prepared with higher molecular weight mPEG (40 kDa). For conjugates prepared with moderate-to-high molecular weight mPEG (10 to 20 kDa), partial compensation of inactivation could be achieved by the inclusion of a reducible disulfide bond, which provides a mechanism to liberate the S10 from the polymer. Grafting multiple copies of S10 to a high-molecular-weight multiarmed PEG (40 kDa) improved GFP-NLS delivery efficiency. However, these constructs were more cytotoxic than the native peptide. Considering that PEGylation could be harnessed for altering the pharmacokinetics and biodistribution profiles of peptide-based delivery agents in vivo, the trends observed herein provide new perspectives on how to manipulate the membrane permeabilization process, which is an important variable for achieving delivery.

Objective: Racism acts as a major barrier to accessing health services for Indigenous communities in Canada, often leading to delayed, avoided or lack of treatment altogether. The Métis population is uniquely positioned in urban settings, as they experience discrimination from both Indigenous and mainstream health and social services due to Canada's long colonial history that is ongoing. Yet, Métis are often left out of discussions regarding racism and health service access. This study explores the experiences of racism and health service access among Métis peoples in Victoria, British Columbia., Methods: We allied a conversational interview method to explore and understand experiences of self-identifying Métis women, Two-Spirit and gender diverse people ( n = 24) who access health and social services in Victoria. Data analysis followed Flicker and Nixon's six-stage DEPICT model., Results: In this paper, we share the experiences of racism and discrimination of those who accessed health and social services in Victoria, British Columbia Such experiences include passing as White, experiencing racism following Métis identity disclosure and witnessing racism. Passing as White was viewed as a protective factor against discrimination as well as harming participants' sense of identity. Experiences of racism took the form of discriminatory comments, harassment and mistreatment, which influenced the willingness of disclosing Métis identity. Witnessing racism occurred in participants, personal and professional lives, negatively impacting them in indirect ways. Each experience of racism had a negative influence on participants' wellbeing and shaped their experience of accessing health and social services., Conclusions: Métis people confront racism and discrimination when attempting to access health and social services through first-hand experiences, witnessing and/or avoidance. While this study contributes to the all too often unacknowledged voices of Métis in Canada, there is a continued need for Métis-specific research to accurately inform policy and practice.

Abdominal radiography is an important diagnostic to detect uroliths. Cystine and urate uroliths were historically characterized as nonmineral opaque on survey radiographs. However, recent research and clinical observations indicate that pure urate and cystine uroliths may be detected with digital radiography. The primary purpose of this prospective, in vitro, diagnostic accuracy study was to determine the sensitivity of digital radiography in detecting cystoliths of varying size and composition. Forty canine uroliths of pure composition (10 each of calcium oxalate, struvite, cystine, and urate), acquired from Minnesota Urolith Center and ranging from 1 to 10 mm, were placed in phantoms of three various sizes and radiographed. The radiographs, including three sets of each urolith separately, were evaluated by three blinded radiologists on two separate occasions. Evaluation included presence or absence of urolith, number of uroliths, and maximum diameter of the urolith(s). For all four types of uroliths and all readers, the specificity and PPV were 100% with an associated very high sensitivity (94.4%-98.9%) and NPV (94.8%-98.9%). Calcium oxalate uroliths were the most accurately measured and struvite were the least accurately measured when compared with the gross measurement. Smaller uroliths were more accurately measured than larger uroliths. Uroliths placed in smaller bladder phantoms were more accurately measured than in larger bladder phantoms. Though accurate measurement of uroliths is complicated by and dependent on numerous variables, our results reveal that urate and cystine uroliths are visualized on digital radiography making them a relevant differential diagnosis when seen clinically., (© 2023 American College of Veterinary Radiology.)

The Southern Ocean greatly contributes to the regulation of the global climate by controlling important heat and carbon exchanges between the atmosphere and the ocean. Rates of climate change on decadal timescales are therefore impacted by oceanic processes taking place in the Southern Ocean, yet too little is known about these processes. Limitations come both from the lack of observations in this extreme environment and its inherent sensitivity to intermittent processes at scales that are not well captured in current Earth system models. The Southern Ocean Carbon and Heat Impact on Climate programme was launched to address this knowledge gap, with the overall objective to understand and quantify variability of heat and carbon budgets in the Southern Ocean through an investigation of the key physical processes controlling exchanges between the atmosphere, ocean and sea ice using a combination of observational and modelling approaches. Here, we provide a brief overview of the programme, as well as a summary of some of the scientific progress achieved during its first half. Advances range from new evidence of the importance of specific processes in Southern Ocean ventilation rate (e.g. storm-induced turbulence, sea-ice meltwater fronts, wind-induced gyre circulation, dense shelf water formation and abyssal mixing) to refined descriptions of the physical changes currently ongoing in the Southern Ocean and of their link with global climate. This article is part of a discussion meeting issue 'Heat and carbon uptake in the Southern Ocean: the state of the art and future priorities'.

We report a single-end forward-pumped fiber laser with a record high output power of 3 kW. The laser is assembled exclusively from commercially widespread components such as the Yb-doped fiber with core/cladding diameter of 20/400 µm, pump laser diodes at an emission wavelength of 915 nm, and a signal and pump fiber combiner that serves as the pump recycler. The record high power arises from the combination of the 915 nm pumping and pump recycler with an effective reflectivity of 78%, increasing simultaneously the thresholds for stimulated Raman scattering and transverse mode instability (TMI). The length of the oscillator was also varied experimentally from 20 m to 5 m, showing a contrast of up to 19% in the TMI threshold. This shows the importance of accurately partitioning the Yb-doped fiber length in between the oscillator and amplifier sections to minimize the impact of TMI.

Despite its central role in the global climate, the Southern Ocean circulation is still one of the least understood ocean circulation systems of the planet. One major constraint to our understanding of this region is the challenge of observing ocean circulation in the seasonally sea ice sector of the Southern Ocean. Here, we present a new Sea Level Anomaly (SLA) product, focusing on the subpolar Southern Ocean and including its sea ice covered parts from 2013 to 2019. Combining observations from multiple satellites, including Cryosat-2, Sentinel-3A, and SARAL/AltiKa, processed with state-of-the-art algorithms, allows an improvement in spatial and temporal resolution compared with previous products. Validation is made by comparing our estimate with existing SLA products, cross-comparing estimates from individual satellites in the sea ice zones, and comparing the time series of the product with a Bottom Pressure Recorder in the Drake Passage., (© 2022. The Author(s).)

Background: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the standard in the diagnosis of solid pancreatic lesions, in particular when combined with rapid onsite evaluation of cytopathology (ROSE). More recently, a fork-tip needle for core biopsy (FNB) has been shown to be associated with excellent diagnostic yield. EUS-FNB alone has however not been compared with EUS-FNA + ROSE in a large clinical trial. Our aim was to compare EUS-FNB alone to EUS-FNA + ROSE in solid pancreatic lesions., Methods: A multicenter, non-inferiority, randomized controlled trial involving seven centers was performed. Solid pancreatic lesions referred for EUS were considered for inclusion. The primary end point was diagnostic accuracy. Secondary end points included sensitivity/specificity, mean number of needle passes, and cost., Results: 235 patients were randomized: 115 EUS-FNB alone and 120 EUS-FNA + ROSE. Overall, 217 patients had malignant histology. The diagnostic accuracy for malignancy of EUS-FNB alone was non-inferior to EUS-FNA + ROSE at 92.2 % (95 %CI 86.6 %-96.9 %) and 93.3 % (95 %CI 88.8 %-97.9 %), respectively ( P  = 0.72). Diagnostic sensitivity for malignancy was 92.5 % (95 %CI 85.7 %-96.7 %) for EUS-FNB alone vs. 96.5 % (93.0 %-98.6 %) for EUS-FNA + ROSE ( P  = 0.46), while specificity was 100 % in both. Adequate histological yield was obtained in 87.5 % of the EUS-FNB samples. The mean (SD) number of needle passes and procedure time favored EUS-FNB alone (2.3 [0.6] passes vs. 3.0 [1.1] passes [ P  < 0.001]; and 19.3 [8.0] vs. 22.7 [10.8] minutes [ P  = 0.008]). EUS-FNB alone cost on average 45 US dollars more than EUS-FNA + ROSE., Conclusion: EUS-FNB alone is non-inferior to EUS-FNA + ROSE and is associated with fewer needle passes, shorter procedure time, and excellent histological yield at comparable cost., Competing Interests: Yen-I Chen, Avijit Chatterjee, Ian Gan, and Fergal Donnellan are consultants for Boston Scientific. Alan Barkun is a consultant for Pendopharm Inc., Boston Scientific Inc., Olympus Inc., Cook Inc., and ATGen Inc. Clarence Wong is a consultant for Boston Scientific and Medtronic Medical. The remaining authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

The extent to which socioeconomic status was associated with life expectancy in the 19 th and early part of the twentieth century is poorly understood. We sought to determine the association between a deceased individual's tombstone size, a potential marker of socioeconomic status, and their age of death in the late modern period. We conducted a cross-sectional study of 276 deceased individuals buried between 1820 and 1992 in a large cemetery in Quebec, Canada. The main outcome measure was age of death. We used generalized linear models adjusted for sex, marital status, and year of death to determine whether tombstone height and volume were associated with a greater number of years lived. Tombstone height and volume were associated with an older age of death in adjusted regression models. Individuals with tall tombstones lived 9.6 years longer than those with short tombstones (95% confidence interval, CI 3.9 to 15.4). Individuals with large volume tombstones lived 6.2 years longer than those with small tombstones (95% CI 1.7 to 10.8). Our findings indicate that in the 1800s and early 1900s, tombstone size was strongly associated with age of death. A possible explanation for this occurrence is that wealthy individuals, capable of purchasing more sizeable tombstones, were more likely to live a longer and healthier life., (© 2021. Springer Nature B.V.)

Background: Awareness of exocrine pancreatic insufficiency (EPI) in cats has increased since the development of an assay for feline trypsin-like immunoreactivity (fTLI). Ultrasound findings in cats with EPI have only been reported rarely and described as nonspecific., Hypothesis/objectives: To describe the ultrasonographic findings, clinical signs, and concurrent diseases in cats with EPI., Animals: Twenty-two client-owned cats with EPI., Methods: Multicenter retrospective descriptive study including cats with serum fTLI concentration ≤8 μg/L and an abdominal ultrasound examination performed within 6 weeks of fTLI measurement. Sonographic measurements of maximal pancreatic thickness and maximal pancreatic duct diameter as well as ratios of pancreatic duct diameter to pancreatic thickness were obtained. Additional sonographic findings, concurrent conditions, and clinical signs were recorded., Results: The most common clinical sign was weight loss (15/22 cats). Chronic enteropathy was the most common concurrent disease (13/22 cats). In 39% of cats, the pancreas had minimal or no sonographic alterations. Pancreatic duct dilatation (>2.5 mm), pancreatic duct tortuosity with variable diameter, or both were seen in 6/13 cats. The pancreatic parenchyma was subjectively thin in 6 cats. A significant relationship was found between subjectively thin pancreatic parenchyma and increased pancreatic duct size : pancreatic thickness ratio (P = .004). Diffuse gastrointestinal dilatation with echogenic content was observed in 8/22 cats., Conclusion: Exocrine pancreatic insufficiency often causes minimal to no sonographic pancreatic changes. Nonetheless, the findings of thin pancreatic parenchyma, pancreatic duct dilatation, or diffuse small intestinal dilatation with echogenic contents in cats with unexplained weight loss or unformed feces should raise clinical suspicion for EPI., (© 2021 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)