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Primary sclerosing cholangitis (PSC) is a rare autoimmune bile duct disease that is strongly associated with immune-mediated disorders. In this study, we implemented multitrait joint analyses to genome-wide association summary statistics of PSC and numerous clinical and epidemiological traits to estimate the genetic contribution of each trait and genetic correlations between traits and to identify new lead PSC risk-associated loci. We identified seven new loci that have not been previously reported and one new independent lead variant in the previously reported locus. Functional annotation and fine-mapping nominated several potential susceptibility genes such as MANBA and IRF5 . Network-based in silico drug efficacy screening provided candidate agents for further study of pharmacological effect in PSC. The genetic basis of primary sclerosing cholangitis has only been partially uncovered. Here, the authors perform a multitrait genome-wide association study to provide insight into the genetic etiology of primary sclerosing cholangitis risk and possible therapeutic drug targets.

Background and Aims: This systematic review and meta-analysis aims to compare the performance of UroVysion® FISH based on the different definitions of a positive result used in published literature with the goal of determining the optimal FISH definition for detecting pancreaticobiliary malignancy. Methods: A systematic literature search identified studies from database inception to Sept 2024 that evaluated the diagnostic performance of FISH in determining malignancy among patients with biliary strictures. All thresholds for positive FISH, as defined by the individual study, were included in this review. Subgroup analysis was performed based on the definitions of positive FISH as follows: (1) polysomy only; (2) polysomy, tetrasomy, or trisomy; and (3) polysomy or 9p deletion. Results: Eighteen studies comprising 2516 FISH specimens were analyzed, including 1133 (45.0%) with malignancy. Using a threshold for positivity as defined in individual studies, the overall sensitivity of FISH was 57.6% (95% confidence interval [CI], 49.4–65.4%), and the overall specificity was 87.8% (95% CI, 79.2–93.2%). Subgroup analysis showed that polysomy as the threshold for positive FISH yielded a sensitivity of 49.4% (95% CI, 43.2–55.5%), with an increased specificity of 96.2% (95% CI, 92.7–98.1%), while polysomy + tetrasomy/trisomy as positive FISH resulted in an increased sensitivity of 64.3% (95% CI 55.4–72.2%) but a decreased specificity of 78.9% (95% CI 64.4–88.5%). The addition of 9p deletion to polysomy as the criteria for a positive test resulted in a non-significant increase in sensitivity (54.7% (95% CI 42.4–66.5%) while maintaining specificity (95.1% (95% CI 84.0–98.6%). Conclusions: Based on these findings, polysomy only or polysomy/9p deletion should be considered as the criterion for defining a positive FISH test to improve diagnostic sensitivity while maintaining high specificity.

Background and Aim. Early identification of malignant biliary strictures (MBS) is challenging, with up to 20% classified as indeterminants after preliminary testing and tissue sampling with endoscopic retrograde cholangiopancreatography (ERCP). We aimed to evaluate the use of methylated DNA markers (MDM) from biliary brushings to enhance MBS detection in a prospective cohort.Methods. Candidate MDMs were evaluated for their utility in MBS diagnosis through a series of discovery and validation phases. DNA was extracted from biliary brushing samples, quantified, bisulfite-converted, and then subjected to methylation-specific Droplet Digital Polymerase Chain Reaction (ddPCR). Patients were considered to have no malignancy if the sampling was negative and there was no evidence of malignancy after 1 year or definitive negative surgical histopathology. Results. Fourteen candidate MDMs were evaluated in the discovery phase, with top-performing and new markers evaluated in the technical validation phase. The top four MDMs were TWIST1, HOXA1, VSTM2B, and CLEC11A, which individually achieved AUC values of 0.82, 0.81, 0.83, and 0.78, respectively, with sensitivities of 59.4%, 53.1%, 62.5%, and 50.0%, respectively, at high specificities for malignancy of 95.2-95.3% for the final biologic validation phase. When combined as a panel, the AUC was 0.86, achieving 73.4% sensitivity and 92.9% specificity, which outperformed cytology and fluorescent in situ hybridization (FISH).Conclusions. The selected methylated DNA markers demonstrated improved performance characteristics for the detection of MBS compared to cytology and FISH. Therefore, MDMs should be considered viable candidates for inclusion in diagnostic testing algorithms.

Access to scanners for magnetic resonance imaging (MRI) is typically limited by cost and by infrastructure requirements. Here, we report the design and testing of a portable prototype scanner for brain MRI that uses a compact and lightweight permanent rare-earth magnet with a built-in readout field gradient. The 122-kg low-field (80 mT) magnet has a Halbach cylinder design that results in a minimal stray field and requires neither cryogenics nor external power. The built-in magnetic field gradient reduces the reliance on high-power gradient drivers, lowering the overall requirements for power and cooling, and reducing acoustic noise. Imperfections in the encoding fields are mitigated with a generalized iterative image reconstruction technique that leverages previous characterization of the field patterns. In healthy adult volunteers, the scanner can generate T1-weighted, T2-weighted and proton density-weighted brain images with a spatial resolution of 2.2 × 1.3 × 6.8 mm 3 . Future versions of the scanner could improve the accessibility of brain MRI at the point of care, particularly for critically ill patients. A portable prototype scanner for brain MRI that uses a compact and lightweight permanent rare-earth magnet with a built-in readout field gradient generates clinically relevant images of the brain, as shown in adult volunteers.

Evidence-based practice (EBP) combines the best available evidence with clinician expertise and patient preference to improve patient outcomes. Recent evidence indicates that Canadian Naturopathic Doctors (NDs) are interested in EBP skill development. The primary objective of the present study was to assess the feasibility and acceptability of a co-designed EBP Continuing Education (CE) course for Canadian NDs. Secondary objectives included assessing changes in EBP skill, use, attitudes, and knowledge. The CE course was evaluated using a pre-post design involving licensed Canadian NDs. The CE course consisted of five weekly, one-hour sessions that were delivered virtually. On course completion, participants reported on their level of satisfaction and provided suggestions for improvement. EBP skill, attitudes and use were assessed using the validated Evidence-Based Practice Attitudes and Utilization Survey. EBP knowledge was objectively assessed using a quiz. Changes in EBP skill, attitudes, use and knowledge were compared between baseline and the end of the course. Use of evidence was reassessed at a 2-month follow up. Sixty-one NDs met eligibility criteria. Eighty-nine percent of participants agreed or strongly agreed that they were satisfied with the course. There was a significant increase in self-reported skill and objectively measured EBP knowledge, but no substantive change in EBP attitudes or use of evidence over time. Some participants indicated the level of difficulty was too high while others reported that it could have been more difficult. Participants also wanted more opportunities to practice the skills being taught in the course. Delivery of the co-designed EBP CE course was found to be both feasible and acceptable. Preliminary evidence suggests that participation in the course was associated with improvements in EBP knowledge and skill. Participants provided actionable suggestions to improve the course in future iterations.

We document the density and hydrologic properties of bare, ablating ice in a mid-elevation (1215 m a.s.l.) supraglacial internally drained catchment in the Kangerlussuaq sector of the western Greenland ice sheet. We find low-density (0.43–0.91 g cm−3, μ = 0.69 g cm−3) ice to at least 1.1 m depth below the ice sheet surface. This near-surface, low-density ice consists of alternating layers of water-saturated, porous ice and clear solid ice lenses, overlain by a thin (< 0.5 m), even lower density (0.33–0.56 g cm−3, μ = 0.45 g cm−3) unsaturated weathering crust. Ice density data from 10 shallow (0.9–1.1 m) ice cores along an 800 m transect suggest an average 14–18 cm of specific meltwater storage within this low-density ice. Water saturation of this ice is confirmed through measurable water levels (1–29 cm above hole bottoms, μ = 10 cm) in 84 % of cryoconite holes and rapid refilling of 83 % of 1 m drilled holes sampled along the transect. These findings are consistent with descriptions of shallow, depth-limited aquifers on the weathered surface of glaciers worldwide and confirm the potential for substantial transient meltwater storage within porous low-density ice on the Greenland ice sheet ablation zone surface. A conservative estimate for the  ∼  63 km2 supraglacial catchment yields 0.009–0.012 km3 of liquid meltwater storage in near-surface, porous ice. Further work is required to determine if these findings are representative of broader areas of the Greenland ice sheet ablation zone, and to assess the implications for sub-seasonal mass balance processes, surface lowering observations from airborne and satellite altimetry, and supraglacial runoff processes.

Climatic variation alters biochemical and ecological processes, but it is difficult both to quantify the magnitude of such changes, and to differentiate long-term shifts from inter-annual variability. Here, we simultaneously quantify decade-scale isotopic variability at the lowest and highest trophic positions in the offshore California Current System (CCS) by measuring δ15N and δ13C values of amino acids in a top predator, the sperm whale (Physeter macrocephalus). Using a time series of skin tissue samples as a biological archive, isotopic records from individual amino acids (AAs) can reveal the proximate factors driving a temporal decline we observed in bulk isotope values (a decline of ≥1 ‰) by decoupling changes in primary producer isotope values from those linked to the trophic position of this toothed whale. A continuous decline in baseline (i.e., primary producer) δ15N and δ13C values was observed from 1993 to 2005 (a decrease of ∼4‰ for δ15N source-AAs and 3‰ for δ13C essential-AAs), while the trophic position of whales was variable over time and it did not exhibit directional trends. The baseline δ15N and δ13C shifts suggest rapid ongoing changes in the carbon and nitrogen biogeochemical cycling in the offshore CCS, potentially occurring at faster rates than long-term shifts observed elsewhere in the Pacific. While the mechanisms forcing these biogeochemical shifts remain to be determined, our data suggest possible links to natural climate variability, and also corresponding shifts in surface nutrient availability. Our study demonstrates that isotopic analysis of individual amino acids from a top marine mammal predator can be a powerful new approach to reconstructing temporal variation in both biochemical cycling and trophic structure.

Much work has shown that the environment can induce non-genetic changes in phenotype that span multiple generations. Theory predicts that predictable environmental variation selects for both increased within- and across-generation responses. Yet, to the best of our knowledge, there are no empirical tests of this prediction. We explored the relationship between within- versus across-generation plasticity by evaluating the influence of predator cues on the life-history traits of Daphnia ambigua. We measured the duration of predator-induced transgenerational effects, determined when transgenerational responses are induced, and quantified the cues that activate transgenerational plasticity. We show that predator exposure during embryonic development causes earlier maturation and increased reproductive output. Such effects are detectable two generations removed from predator exposure and are similar in magnitude in response to exposure to cues emitted by injured conspecifics. Moreover, all experimental contexts and traits yielded a negative correlation between within- versus across-generation responses. That is, responses to predator cues within- and across-generations were opposite in sign and magnitude. Although many models address transgenerational plasticity, none of them explain this apparent negative relationship between within- and across-generation plasticities. Our results highlight the need to refine the theory of transgenerational plasticity.

Ponding of meltwater on the surface of the Greenland Ice Sheet has the potential to reduce ice sheet albedo and amplify mass loss. However, this process remains poorly constrained and is absent from models that project ice sheet mass balance. Here we demonstrate that meltwater ponding considerably increases the amount of energy available for melting the Greenland Ice Sheet. We first use satellite-derived products to show that meltwater ponding has a significant impact on spatial albedo patterns, particularly in the lower percolation zone. We then use drone imagery to demonstrate that, in the upper ablation zone, there are thousands of narrow streams and small pools (<100 m²) that collectively account for >50% of the total meltwater area. These small meltwater features are not resolved by surface water maps derived from medium-resolution satellite imagery, signifying that the radiative effect of meltwater ponding is three to four times stronger than predicted by satellite-based approaches. Our findings therefore place lower bounds on the radiative effect of meltwater ponding that could be used to advocate for the inclusion of this process into models that forecast Greenland Ice Sheet’s contribution to sea-level rise. Meltwater ponding reduces Greenland Ice Sheet albedo, but this process is not included in models. This study uses drone imagery to show that small streams and ponds, often missed by satellites, considerably increase the energy available for melt.

Coincident with climate shifts and anthropogenic perturbations, the highly voracious jumbo squid Dosidicus gigas reached unprecedented northern latitudes along the NE Pacific margin post 1997-98. The physical or biological drivers of this expansion, as well as its ecological consequences remain unknown. Here, novel analysis from both bulk tissues and individual amino acids (Phenylalanine; Phe and Glutamic acid; Glu) in both gladii and muscle of D. gigas captured in the Northern California Current System (NCCS) documents for the first time multiple geographic origins and migration. Phe δ(15)N values, a proxy for habitat baseline δ(15)N values, confirm at least three different geographic origins that were initially detected by highly variable bulk δ(15)N values in gladii for squid at small sizes (<30 cm gladii length). In contrast, bulk δ(15)N values from gladii of large squid (>60 cm) converged, indicating feeding in a common ecosystem. The strong latitudinal gradient in Phe δ(15)N values from composite muscle samples further confirmed residency at a point in time for large squid in the NCCS. These results contrast with previous ideas, and indicate that small squid are highly migratory, move into the NCCS from two or more distinct geographic origins, and use this ecosystem mainly for feeding. These results represent the first direct information on the origins, immigration and habitat use of this key \"invasive\" predator in the NCCS, with wide implications for understanding both the mechanisms of periodic D. gigas population range expansions, and effects on ecosystem trophic structure.