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BackgroundAccording to the new AASLD Practice Guidance, all patients with primary sclerosing cholangitis (PSC) should be considered for participation in clinical trials. However, PSC's rarity has posed challenges to characterizing patient interest in trial participation and identifying predictors of patient willingness to participate in drug trials.MethodsPSC Partners Seeking a Cure developed the "Our Voices" survey to inform the development of the Externally-Led Patient-Focused Drug Development Forum, an FDA initiative to capture patient experiences and perspectives on drug development.ResultsOf 797 survey respondents from over 30 countries, 536 (67%) identified slowing disease progression as the most important outcome. Eighty-nine percent identified their hepatologist/gastroenterologist as someone they would approach for advice about trials. Although 61% reported being willing to participate in drug trials, only 26% had ever been asked to participate. Notable barriers to trial involvement included unknown long-term risks (71%), long travel times to the study center (32%), and a liver biopsy requirement (27%). On multivariable logistic regression, pruritus (OR 1.62, 95% CI: 1.09-2.40, p = 0.017) was positively associated with willingness to participate in disease-modifying therapy trials, while jaundice (OR 0.34, 95% CI: 0.19-0.61, p < 0.001) and inflammatory bowel disease (OR 0.64, 95% CI: 0.42-0.98, p = 0.038) were negatively associated. Pruritus (OR 2.25, 95% CI: 1.50-3.39, p < 0.001) was also independently associated with willingness to participate in symptom treatment trials.ConclusionsMost patients with PSC report interest in participating in clinical trials, but few have been asked to participate. Referral of patients with PSC by their hepatologist/gastroenterologist to clinical trials and patient education on trial participation are vital to closing the gap between trial interest and participation. Pruritus may serve as a key indicator of patient interest in trial participation.

Background and aims Design Setting Participants Intervention and comparator Measurement Findings Conclusion A 12‐week placebo‐controlled, sequential parallel Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT‐2) trial evaluated the effects of extended‐release injectable naltrexone plus extended‐release oral bupropion (NTX + BUPN) on methamphetamine (MA) use over two stages. This study reports on the previously unpublished stage 2 MA use in participants randomized at stage 1 to receive NTX + BUPN through both stages compared with those assigned to placebo.This is a secondary analysis of the US National Institute on Drug Abuse (NIDA) ADAPT‐2 network trial.The parent ADAPT‐2 trial was carried out across multiple NIDA Clinical Trials Network (CTN) sites in the United States.This analysis includes 403 people with MA use disorder who participated in the ADAPT‐2 CTN trial.NTX + BUPN was compared with placebo over the course of the trial.MA use was measured by urine drug screens conducted twice weekly for 12 weeks, then once in week 13 and once in week 16 post‐treatment follow‐up.Participants on NTX + BUPN in stage 1 showed an additional 9.2% increase [95% confidence interval (CI), 0.09%–17.9%, P = 0.038] during stage 2 in their probability of testing negative for MA, with a total increase of 27.1% (95% CI, 13.2%–41.1%, P < 0.001) over the full 12 weeks of treatment. In contrast, participants on placebo in both stages increased in probability of testing MA‐negative by a total of 11.4% (95% CI, 4.1%–18.6%, P = 0.002) over all 12 weeks. The 12‐week increase among participants on NTX + BUPN was significantly greater—by 15.8% (95% CI, 4.5%–27.0%, P = 0.006)—than the increase among those on placebo.For people with methamphetamine (MA) use disorder receiving treatment with extended‐release injectable naltrexone plus extended‐release oral bupropion (NTX + BUPN), continued treatment with NTX + BUPN after 6 weeks is associated with additional reductions in MA use up to 12 weeks. [ABSTRACT FROM AUTHOR]

The evolution of submarine canyons is primarily controlled by turbidity currents, which erode and fill them over time; however, many other hydrodynamic currents operate within canyons. Bottom currents from these other hydrodynamic processes, including internal tides, can be dominant processes, but their deposits are seldom recognized in sediment cores or the rock record. This study combines autonomous underwater vehicle swath bathymetry imagery and sub‐bottom profiles, high‐resolution sediment core analyses (X‐ray imagery and thin sections), and previously collected seabed video and flow measurements within Logan Canyon head (eastern Canada) to provide a detailed, modern record of facies associated with hydrodynamic processes in a canyon head. These results suggest that bottom currents are responsible for maintaining gullies on canyon sidewalls and an axial channel on the canyon floor. Thin sections of sediment cores reveal that muddy sand in the canyon head consists of mud aggregates and silt and fine‐grained sand, both behaving similarly in terms of flow dynamics. Three facies are present at macro‐scale and micro‐scale: laminated, partially laminated and bioturbated sandy mud. Sedimentary structures include rhythmic sand and mud aggregate couplets, planar to wavy laminations, current ripple cross‐laminations and fining‐upward successions, which are attributed to bottom currents induced by internal tides. Bioturbated facies, characterized by discrete biogenic structures and cross‐cutting relationships, predominate and overprint a mottled background. A mottled bioturbation fabric also alternates with or locally disrupts layering within the partially laminated facies. Internal tide currents, capable of bedload transport and forming ripples, were measured during a monitoring period in the canyon head, followed by rapid re‐establishment of benthos and associated biogenic structures, supporting the core interpretations. Preservation of sedimentary facies associated with these internal tides occurs when the sedimentation rate outpaces the rate of bioturbation, likely during stormier conditions on the shelf. These results represent observations of sedimentary facies associated with modern bottom currents and internal tides, and can be used to interpret similar occurrences within the rock record. [ABSTRACT FROM AUTHOR]

Here, we report recurrent focal deletions of the chr14q32.31- 32 locus, including TRAF3, a negative regulator of NF- kB signaling, in de novo diffuse large B cell lymphoma (DLBCL) (24/324 cases). Integrative analysis revealed an association between TRAF3 copy number loss with accumulation of NIK, the central noncanonical (NC) NF- kB kinase, and increased NC NF- kB pathway activity. Accordingly, TRAF3 genetic ablation in isogenic DLBCL model systems caused upregulation of NIK and enhanced NC NF- kB downstream signaling. Knockdown or pharmacological inhibition of NIK in TRAF3- deficient cells differentially impaired their proliferation and survival, suggesting an acquired onco- addiction to NC NF- kB. TRAF3 ablation also led to exacerbated secretion of the immunosuppressive cytokine IL- 10. Coculturing of TRAF3- deficient DLBCL cells with CD8+ T cells impaired the induction of Granzyme B and interferon (IFN) γ, which were restored following neutralization of IL- 10. Our findings corroborate a direct relationship between TRAF3 genetic alterations and NC NF- kB activation, and highlight NIK as a potential therapeutic target in a defined subset of DLBCL. [ABSTRACT FROM AUTHOR]

In the era of free flap reconstruction, mandibular defects are routinely reconstructed with osseous free flaps, and non‐free flap bony reconstruction options are limited. A patient with T4N0 mandibular squamous cell carcinoma underwent resection with fibula free flap reconstruction of a parasymphyseal to angle defect. After free flap failure due to venous congestion, the flap was explanted. He declined additional free flap reconstruction and elected to proceed with pedicled osteomyocutaneous pectoralis major with rib. In this case presentation, we discuss the technical details of harvest of this flap using the 6th rib. The pedicled osteomyocutaneous pectoralis major flap with osseous rib harvest, which is infrequently described in the literature, remains a viable option for bony reconstruction, particularly in the salvage setting. [ABSTRACT FROM AUTHOR]

In this study, we employ a dual-objective optimization model, utilizing the Implicit Modified Coverage Location Problem (MCLP-Implicit) approach, to determine an appropriate fire station allocation. Our objectives encompass maximizing coverage in areas with a heightened projected demand, based on socioeconomic predictors of building fires, and concurrently minimizing the distance of uncovered demand zones to the closest fire station. The challenges of this model reflect the criticality of strategic placement, aiming for not just swift response times but also the complete coverage of a region with priority given to subregions with a pronounced potential for incidents. The applicability of the proposed approach is demonstrated through a case study in south-east Queensland. Our findings indicate that there is a tangible justification for adopting this model. The broader coverage and wider spread of locations it produces can greatly aid in the dynamic deployment of personnel during surges caused by seasonal fluctuations or unforeseen calamities. By weaving in socioeconomic aspects into demand predictions, our model has also maintained appropriate coverage to socioeconomically disadvantaged communities in the region. Nevertheless, it is paramount to underline the recommendation that further research should account for road connectivity—a pivotal factor when pinpointing these locations in the real world. This research paves the way for enriched insights in long-term urban planning and fire response protocol crafting, especially in regions mirroring similar socioeconomic profiles or risks of natural disasters, not to mention its commercial implications to the relevant industry servicing the fire and rescue authorities. [ABSTRACT FROM AUTHOR]