Winter GPS tagging reveals home ranges during the breeding season for a boreal-nesting migrant songbird, the Golden-crowned Sparrow.

Determining space use for species is fundamental to understanding their ecology, and tracking animals can reveal insights into their spatial ecology on home ranges and territories. Recent technological advances have led to GPS-tracking devices light enough for birds as small as ~30 g, creating novel opportunities to remotely monitor fine-scale movements and space use for these smaller species. We tested whether miniaturized GPS tags can allow us to understand space use of migratory birds away from their capture sites and sought to understand both pre-breeding space use as well as territory and habitat use on the breeding grounds. We used GPS tags to characterize home ranges on the breeding grounds for a migratory songbird with limited available breeding information, the Golden-crowned Sparrow (Zonotrichia atricapilla). Using GPS points from 23 individuals across 26 tags (three birds tagged twice), we found home ranges in Alaska and British Columbia were on average 44.1 ha (95% kernel density estimate). In addition, estimates of territory sizes based on field observations (mean 2.1 ha, 95% minimum convex polygon [MCP]) were three times smaller than 95% MCPs created using GPS tags (mean 6.5 ha). Home ranges included a variety of land cover classes, with shrubland particularly dominant (64-100% of home range cover for all but one bird). Three birds tracked twice returned to the same breeding area each year, supporting high breeding site fidelity for this species. We found reverse spring migration for five birds that flew up to 154 km past breeding destinations before returning. GPS-tracking technology allowed for critical ecological insights into this migratory species that breeds in very remote locations.

RhoGEF Tiam2 regulates glutamatergic synaptic transmission in hippocampal CA1 pyramidal neurons.

Glutamatergic synapses exhibit significant molecular diversity but circuit-specific mechanisms that underlie synaptic regulation are not well characterized. Prior reports show that RhoGEF Tiam1 regulates perforant path-dentate gyrus (DG) granule neuron synapses. In the present study, we report Tiam1's homolog Tiam2 is implicated in glutamatergic neurotransmission at CA1 pyramidal neurons. We find that Tiam2 regulates evoked excitatory glutamatergic currents via a post-synaptic mechanism mediated by the catalytic Dbl-homology domain. Overall, we present evidence for RhoGEF Tiam2's role in glutamatergic synapse function at Schaffer-collateral-CA1 pyramidal neuron synapses.Significance statement Glutamatergic synapses are known to vary in composition and function but how this heterogeneity is established to create input-specific synaptic diversity is not well understood. In the present study we show Tiam2 regulates glutamatergic neurotransmission at Schaffer-collateral-CA1 pyramidal neuron synapses. We find that this function is dependent on its catalytic domain. By contrast we did not observe a role for Tiam2 in synaptic transmission at perforant path-DG granule neuron synapses. We also find that Tiam1 and Tiam2 are individually dispensable for functional synaptic plasticity in CA1 pyramidal neurons. To our knowledge, this is the first evidence of the RhoGEF Tiam2's role in regulating glutamatergic synapses.

In vitro activity of taurolidine against clinical Candida auris isolates: relevance to catheter-related bloodstream infections.

Candida auris is an evolving and concerning global threat. Of particular concern are bloodstream infections related to central venous catheters. We evaluated the activity of taurolidine, a broad-spectrum antimicrobial in catheter lock solutions, against 106 C. auris isolates. Taurolidine was highly active with a MIC50/MIC90 of 512/512 mg/L, over 20-fold lower than lock solution concentrations of ≥13,500 mg/L. Our data demonstrate a theoretical basis for taurolidine-based lock solutions for prevention of C. auris catheter-associated infections.

Cooperation and competition between denitrification and chromate reduction in a hydrogen-based membrane biofilm reactor.

Competition and cooperation between denitrification and Cr(VI) reduction in a H2-based membrane biofilm reactor (H2-MBfR) were documented over 55 days of continuous operation. When nitrate (5 mg N/L) and chromate (0.5 mg Cr/L) were fed together, the H2-MBfR maintained approximately 100 % nitrate removal and 60 % chromate Cr(VI) removal, which means that nitrate outcompeted Cr(VI) for electrons from H2 oxidation. Removing nitrate from the influent led to an immediate increase in Cr(VI) removal (to 92 %), but Cr(VI) removal gradually deteriorated, with the removal ratio dropping to 14 % after five days. Cr(VI) removal resumed once nitrate was again added to the influent. 16S rDNA analyses showed that bacteria able to carry out H2-based denitrification and Cr(VI) reduction were in similar abundances throughout the experiment, but gene expression for Cr(VI)-reduction and export shifted. Functional genes encoding for energy-consuming chromate export (encoded by ChrA) as a means of bacterial resistance to toxicity were more abundant than genes encoding for the energy producing Cr(VI) respiration via the chromate reductase ChrR-NdFr. Thus, Cr(VI) transport and resistance to Cr(VI) toxicity depended on H2-based denitrification to supply energy. With Cr(VI) being exported from the cells, Cr(VI) reduction to Cr(III) was sustained. Thus, cooperation among H2-based denitrification, Cr(VI) export, and Cr(VI) reduction led to sustained Cr(VI) removal in the presence of nitrate, even though Cr(VI) reduction was at a competitive disadvantage for utilizing electrons from H2 oxidation.

Qualitative and Psychometric Evaluation of PROMIS®-29 to Assess General Health-Related Quality of Life in Patients With Moderately to Severely Active Inflammatory Bowel Disease.

OBJECTIVES: To evaluate content validity and psychometric properties of the 29-item Patient-Reported Outcomes Measurement Information System® (PROMIS-29) to determine its suitability in inflammatory bowel disease (IBD) clinical trials. METHODS: Content validity of PROMIS-29 was evaluated using qualitative interviews, including concept elicitation and cognitive debriefing, among patients living with Crohn's disease (CD, N=20) or ulcerative colitis (UC, N=19). PROMIS-29 validity, reliability, and responsiveness were assessed using data from phase 2 clinical trials of CD (N=360) and UC (N=518). RESULTS: Common (≥74%) symptoms reported in qualitative interviews were increased stool frequency, fatigue, abdominal pain/cramping, blood/mucus in stool, bowel urgency, and diarrhea. Disease impact aligned with PROMIS-29 content (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles/activities). Cognitive debriefing indicated PROMIS-29 instructions were easily understood, items were relevant, and the recall period was appropriate. Psychometric evaluations demonstrated PROMIS-29 scores indicating worse symptoms/functioning were associated with lower health-related quality of life (HRQoL) and greater disease activity and severity. PROMIS-29 domain scores correlated (rs≥0.40) with Inflammatory Bowel Disease Questionnaire domains and EuroQol-5 Dimension-5 Level dimensions measuring similar concepts. Test-retest reliability among patients with stable disease was moderate-to-excellent (0.64-0.94) for nearly all domains in all studies. PROMIS-29 was responsive to change in disease status from baseline to Week 12. Thresholds for clinically meaningful improvement ranged from ≥3 to ≥8, depending on domain. CONCLUSION: PROMIS-29 is valid, reliable, and responsive for assessing general HRQoL and treatment response in IBD clinical trials.

Nitinol Staple Use in Primary Arthrodesis of Lisfranc Fracture-Dislocations.

BACKGROUND: Primary arthrodesis of Lisfranc fracture-dislocations is a reliable treatment option, yet concerns remain about nonunion. Nitinol staple use has recently proliferated in midfoot arthrodesis. The purpose of this study is to examine the union rate of primary arthrodesis of acute Lisfranc fracture-dislocations treated with nitinol staples compared with traditional plate-and-screw fixation. The secondary objective is to assess the difference in operative times and reoperation rates. METHODS: Midfoot fracture-dislocations treated with primary arthrodesis by 7 foot and ankle orthopaedic surgeons were reviewed. Of 160 eligible patients, 121 patients (305 joints) met the required 4-month minimum radiographic follow-up. Radiographic outcomes were analyzed at the individual joint level. Each joint was classified as either staples alone (45 patients, 154 joints), staples plus plates and screws (hybrid) (45 patients, 40 joints), or plates and screws alone (31 patients, 111 joints). The primary outcome was arthrodesis union at each joint fused. RESULTS: Nonunion was more common (9.0%, 10/111) among joints fixed with plate and screws than with hybrid (2.5%, 1/40) or staples only (1.3%, 2/154) (P = .0085). Multivariable regression demonstrated that autograft use was independent associated with union (P = .0035) and plate-and-screw only fixation was an independent risk factor for nonunion (P = .0407). Median operating room and tourniquet times were shorter for hybrid (92 and 83 minutes) and staple only (67 and 63 minutes) constructs compared to plate-and-screw only fixation (105 and 95 minutes) (P ≤ .0001 and .0003). There was no difference in reoperation rates among patients with different fixation types. CONCLUSION: We found that use of nitinol compression staple and bone autograft in primary arthrodesis of Lisfranc and midfoot fracture-dislocations was associated with both improved union rates and shorter tourniquet and operative times compared to traditional plate-and-screw fixation techniques. LEVEL OF EVIDENCE: Level III, therapeutic.

Impact of Prior Biologic or Janus Kinase Inhibitor Therapy on Efficacy and Safety of Etrasimod in the ELEVATE UC 52 and ELEVATE UC 12 Trials.

BACKGROUND AND AIMS: Etrasimod is an oral, once daily, selective sphingosine 1-phosphate [S1P]1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis [UC]. This subgroup analysis evaluated the efficacy and safety of etrasimod 2 mg once daily vs placebo by prior biologic/Janus kinase inhibitor [bio/JAKi] exposure in ELEVATE UC 52 and ELEVATE UC 12. METHODS: Pre-defined efficacy endpoints were assessed at Weeks 12 and 52 in ELEVATE UC 52 and Week 12 in ELEVATE UC 12 in bio/JAKi-naïve and -experienced patients, and at Week 12 [pooled] based on prior advanced therapy exposure mechanism. RESULTS: In the ELEVATE UC 52 and ELEVATE UC 12 analysis populations, 80/274 [29.2%] and 74/222 [33.3%] patients receiving etrasimod and 42/135 [31.1%] and 38/112 [33.9%] patients receiving placebo, respectively, were bio/JAKi-experienced. In both bio/JAKi-naïve and -experienced patients, a significantly greater proportion receiving etrasimod vs placebo achieved clinical remission (p<0.05) in ELEVATE UC 52 at Weeks 12 [naïve: 30.9% vs 9.7%; experienced: 17.5% vs 2.4%] and 52 [naïve: 36.6% vs 7.5%; experienced: 21.3% vs 4.8%]; in ELEVATE UC 12, this was observed only for bio/JAKi-naïve patients [naïve: 27.7% vs 16.2%, p=0.033; experienced: 18.9% vs 13.2%, p=0.349]. Similar patterns were observed for most efficacy endpoints. Among patients with prior anti-integrin exposure [N=90], a significantly greater proportion achieved clinical response [54.1% vs 27.6%, p=0.030], but not clinical remission [9.8% vs 3.4%, p=0.248], with etrasimod vs placebo. CONCLUSIONS: Bio/JAKi-naïve and -experienced patients had clinically meaningful induction and maintenance treatment benefits with etrasimod vs placebo.

Optimized bimetallic ratios for durable membrane catalyst-film reactors in treating nitrate-polluted water.

Nitrate contamination of surface and ground water is a significant global challenge. Most current treatment technologies separate nitrate from water, resulting in concentrated wastestreams that need to be managed. Membrane Catalyst-film Reactors (MCfR), which utilize in-situ produced nanocatalysts attached to hydrogen-gas-permeable hollow-fiber membranes, offer a promising alternative for denitrification without generating a concentrated wastestream. In hydrogen-based MCfRs, bimetallic nano-scale catalysts reduce nitrate to nitrite and then further to di-nitrogen or ammonium. This study first investigated how different molar ratios of indium-to-palladium (In:Pd) catalytic films influenced denitrification rates in batch-mode MCfRs. We evaluated eleven In-Pd bimetallic catalyst films, with In:Pd molar ratios from 0.0029 to 0.28. Nitrate-removal exhibited a volcano-shaped dependence on In content, with the highest nitrate removal (0.19 mgNO3--N-min-1 L-1) occurring at 0.045 mol In/mol Pd. Using MCfRs with the optimal In:Pd loading, we treated nitrate-spiked tap water in continuous-flow for >60 days. Nitrate removal and reduction occurred in three stages: substantial denitrification in the first stage, a decline in denitrification efficiency in the second stage, and stabilized denitrification in the third stage. Factors contributing to the slowdown of denitrification were: loss of Pd and In catalysts from the membrane surface and elevated pH due to hydroxide ion production. Sustained nitrate removal will require that these factors be mitigated.

Biogenic Palladium Improved Perchlorate Reduction during Nitrate Co-Reduction by Diverting Electron Flow in a Hydrogenotrophic Biofilm.

Microbial reduction of perchlorate (ClO4-) is emerging as a cost-effective strategy for groundwater remediation. However, the effectiveness of perchlorate reduction can be suppressed by the common co-contamination of nitrate (NO3-). We propose a means to overcome the limitation of ClO4- reduction: depositing palladium nanoparticles (Pd0NPs) within the matrix of a hydrogenotrophic biofilm. Two H2-based membrane biofilm reactors (MBfRs) were operated in parallel in long-term continuous and batch modes: one system had only a biofilm (bio-MBfR), while the other incorporated biogenic Pd0NPs in the biofilm matrix (bioPd-MBfR). For long-term co-reduction, bioPd-MBfR had a distinct advantage of oxyanion reduction fluxes, and it particularly alleviated the competitive advantage of NO3- reduction over ClO4- reduction. Batch tests also demonstrated that bioPd-MBfR gave more rapid reduction rates for ClO4- and ClO3- compared to those of bio-MBfR. Both biofilm communities were dominated by bacteria known to be perchlorate and nitrate reducers. Functional-gene abundances reflecting the intracellular electron flow from H2 to NADH to the reductases were supplanted by extracellular electron flow with the addition of Pd0NPs.

Modeling Ion Transport across Thin-Film Composite Membranes During Saltwater Electrolysis.

Affordable thin-film composite (TFC) membranes are a potential alternative to more expensive ion exchange membranes in saltwater electrolyzers used for hydrogen gas production. We used a solution-friction transport model to study how the induced potential gradient controls ion transport across the polyamide (PA) active layer and support layers of TFC membranes during electrolysis. The set of parameters was simplified by assigning the same size-related partition and friction coefficients for all salt ions through the membrane active layer. The model was fit to experimental ion transport data from saltwater electrolysis with 600 mM electrolytes at a current density of 10 mA cm-2. When the electrolyte concentration and current density were increased, the transport of major charge carriers was successfully predicted by the model. Ion transport calculated using the model only minimally changed when the negative active layer charge density was varied from 0 to 600 mM, indicating active layer charge was not largely responsible for controlling ion crossover during electrolysis. Based on model simulations, a sharp pH gradient was predicted to occur within the supporting layer of the membrane. These results can help guide membrane design and operation conditions in water electrolyzers using TFC membranes.

AMPK-mediated regulation of endogenous cholesterol synthesis does not affect atherosclerosis in a murine Pcsk9-AAV model.

BACKGROUND AND AIMS: Dysregulated cholesterol metabolism is a hallmark of atherosclerotic cardiovascular diseases, yet our understanding of how endogenous cholesterol synthesis affects atherosclerosis is not clear. The energy sensor AMP-activated protein kinase (AMPK) phosphorylates and inhibits the rate-limiting enzyme in the mevalonate pathway HMG-CoA reductase (HMGCR). Recent work demonstrated that when AMPK-HMGCR signaling was compromised in an Apoe-/- model of hypercholesterolemia, atherosclerosis was exacerbated due to elevated hematopoietic stem and progenitor cell mobilization and myelopoiesis. We sought to validate the significance of the AMPK-HMGCR signaling axis in atherosclerosis using a non-germline hypercholesterolemia model with functional ApoE. METHODS: Male and female HMGCR S871A knock-in (KI) mice and wild-type (WT) littermate controls were made atherosclerotic by intravenous injection of a gain-of-function Pcsk9D374Y-adeno-associated virus followed by high-fat and high-cholesterol atherogenic western diet feeding for 16 weeks. RESULTS: AMPK activation suppressed endogenous cholesterol synthesis in primary bone marrow-derived macrophages from WT but not HMGCR KI mice, without changing other parameters of cholesterol regulation. Atherosclerotic plaque area was unchanged between WT and HMGCR KI mice, independent of sex. Correspondingly, there were no phenotypic differences observed in hematopoietic progenitors or differentiated immune cells in the bone marrow, blood, or spleen, and no significant changes in systemic markers of inflammation. When lethally irradiated female mice were transplanted with KI bone marrow, there was similar plaque content relative to WT. CONCLUSIONS: Given previous work, our study demonstrates the importance of preclinical atherosclerosis model comparison and brings into question the importance of AMPK-mediated control of cholesterol synthesis in atherosclerosis.

Characterizing applications, exposure risks, and hazard communication for engineered nanomaterials in construction.

BACKGROUND: Engineered nanomaterials (ENMs) may pose health risks to workers. Objectives were to characterize ENM applications in construction, identify exposure scenarios, and evaluate the quality of safety data sheets (SDSs) for nano-enabled construction products. METHODS: SDSs and product data were obtained from a public database of nano-enabled construction products. Descriptive statistics were calculated for affected trades, product categories, and types of ENMs. A sample of SDSs (n = 33) was evaluated using modified criteria developed by NIOSH researchers. Bulk analysis via transmission electron microscopy characterized nanoparticles in a subset of products. RESULTS: Companies report using >50 ENMs in construction products. ENM composition could not be determined via SDSs for 38.1% of the 907 products examined. Polymers and metal oxides tied for most frequently reported ENMs (n = 87, 9.6%). Nano silica, graphene, carbon nanotubes, and silver nanoparticles were also frequently reported. Most of the products were paints and coatings (n = 483, 53.3%), followed by pre-market additives, cementitious materials, insulation, and lubricants. Workers in twenty construction trades are likely to handle nano-enabled products, these particularly encompass cement and brick masons, painters, laborers, carpenters, glaziers, and insulators. A wide range of exposure scenarios were identified. SDSs were classified as satisfactory (18%), in need of improvement (12%), or in need of significant improvement (70%). Bulk analyses revealed discrepancies between actual ENM composition and those in SDSs. DISCUSSION AND CONCLUSION: There has been significant progress investigating risks to construction workers posed by ENMs, but SDSs need major improvements. This study provides new insights on the use of ENMs in construction, exposure risks, and hazard communication.

Acute severe ulcerative colitis trials: the past, the present and the future.

Acute severe ulcerative colitis (ASUC), characterised by bloody diarrhoea and systemic inflammation, is associated with a significant risk of colectomy and a small risk of mortality. The landmark trial of cortisone in 1955 was pivotal for two reasons: first, for establishing the efficacy of a drug that remains a first-line therapy today and, second, for producing the first set of disease severity criteria and clinical trial endpoints that shaped the subsequent ASUC trial landscape. Trials in the 1990s and at the turn of the millennium established the efficacy of infliximab and ciclosporin, but since then, there has been little progress in drug development for this high-risk population. This systematic review evaluates all interventional randomised controlled trials (RCTs) conducted in patients hospitalised with severe UC. It provides an overview of the efficacy of treatments from past to present and assesses the evolution of trial characteristics with respect to study populations, eligibility criteria and study designs over time. This review details ongoing RCTs in this field and provides a perspective on the challenges for future clinical trial programmes and how these can be overcome to help deliver novel ASUC therapies.

Cryptic diversity within two widespread diadromous freshwater fishes (Teleostei: Galaxiidae).

Identification of taxonomically cryptic species is essential for the effective conservation of biodiversity. Freshwater-limited organisms tend to be genetically isolated by drainage boundaries, and thus may be expected to show substantial cryptic phylogenetic and taxonomic diversity. By comparison, populations of diadromous taxa, that migrate between freshwater and marine environments, are expected to show less genetic differentiation. Here we test for cryptic diversity in Australasian populations (both diadromous and non-diadromous) of two widespread Southern Hemisphere fish species, Galaxias brevipinnis and Galaxias maculatus. Both mtDNA and nuclear markers reveal putative cryptic species within these taxa. The substantial diversity detected within G. brevipinnis may be explained by its strong climbing ability which allows it to form isolated inland populations. In island populations, G. brevipinnis similarly show deeper genetic divergence than those of G. maculatus, which may be explained by the greater abundance of G. maculatus larvae in the sea allowing more ongoing dispersal. Our study highlights that even widespread, 'high-dispersal' species can harbour substantial cryptic diversity and therefore warrant increased taxonomic and conservation attention.

Using a non-precious metal catalyst for long-term enhancement of methane production in a zero-gap microbial electrosynthesis cell.

Microbial electrosynthesis (MES) cells exploit the ability of microbes to convert CO2 into valuable chemical products such as methane and acetate, but high rates of chemical production may need to be mediated by hydrogen and thus require a catalyst for the hydrogen evolution reaction (HER). To avoid the usage of precious metal catalysts and examine the impact of the catalyst on the rate of methane generation by microbes on the electrode, we used a carbon felt cathode coated with NiMo/C and compared performance to a bare carbon felt or a Pt/C-deposited cathode. A zero-gap configuration containing a cation exchange membrane was developed to produce a low internal resistance, limit pH changes, and enhance direct transport of H2 to microorganisms on the biocathode. At a fixed cathode potential of -1 V vs Ag/AgCl, the NiMo/C biocathode enabled a current density of 23 ± 4 A/m2 and a high methane production rate of 4.7 ± 1.0 L/L-d. This performance was comparable to that using a precious metal catalyst (Pt/C, 23 ± 6 A/m2, 5.4 ± 2.8 L/L-d), and 3-5 times higher than plain carbon cathodes (8 ± 3 A/m2, 1.0 ± 0.4 L/L-d). The NiMo/C biocathode was operated for over 120 days without observable decay or severe cathode catalyst leaching, reaching an average columbic efficiency of 53 ± 9 % based on methane production under steady state conditions. Analysis of microbial community on the biocathode revealed the dominance of the hydrogenotrophic genus Methanobacterium (∼40 %), with no significant difference found for biocathodes with different materials. These results demonstrated that HER catalysts improved rates of methane generation through facilitating hydrogen gas evolution to an attached biofilm, and that the long-term enhancement of methane production in MES was feasible using a non-precious metal catalyst and a zero-gap cell design.

Assessment of the antinociceptive, respiratory-depressant, and reinforcing effects of the low pKa fluorinated fentanyl analogs, FF3 and NFEPP.

RATIONALE: Recent studies report that fentanyl analogs with relatively low pKa values produce antinociception in rodents without other mu opioid-typical side effects due to the restriction of their activity to injured tissue with relatively low pH values. However, it is unclear if and to what degree these compounds may produce mu opioid-typical side effects (respiratory depression, reinforcing effects) at doses higher than those required to produce antinociception. OBJECTIVES: The present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pKa values in terms of potency and efficacy in male and female Sprague-Dawley rats. METHODS: Nociception was produced by administration of Complete Freund's Adjuvant into the hind paw of subjects, and antinociception was measured using an electronic Von Frey test. Respiratory depression was measured using whole-body plethysmography. Reinforcing effects were measured in self-administration using a progressive-ratio schedule of reinforcement. The dose ranges tested for each drug encompassed no effect to maximal effects. RESULTS: All compounds produced full effects in all measures but varied in potency. FF3 and fentanyl were equipotent in antinociception and self-administration, but FF3 was less potent than fentanyl in respiratory depression. NFEPP was less potent than fentanyl in every measure. The magnitude of potency difference between antinociception and other effects was greater for FF3 than for NFEPP or fentanyl, indicating that FF3 had the widest margin of safety when relating antinociception to respiratory-depressant and reinforcing effects. CONCLUSIONS: Low pKa fentanyl analogs possess potential as safer analgesics, but determining the optimal degree of difference for pKa relative to fentanyl will require further study due to some differences between the current results and findings from prior work with these analogs.

Implementing Entrustable Professional Activities in Pediatric Fellowships: Facilitating the Process.

BACKGROUND AND OBJECTIVES: Entrustable professional activities (EPAs) will be used for initial certification by the American Board of Pediatrics by 2028. Less than half of pediatric fellowships currently use EPAs for assessment, yet all will need to adopt them. Our objectives were to identify facilitators and barriers to the implementation of EPAs to assess pediatric fellows and to determine fellowship program directors' (FPD) perceptions of EPAs and Milestones. METHODS: We conducted a survey of FPDs from 15 pediatric subspecialties. EPA users were asked about their implementation of EPAs, barriers encountered, and perceptions of EPAs. Nonusers were queried about deterrents to using EPAs. Both groups were asked about potential facilitators of implementation and their perceptions of Milestones. RESULTS: The response rate was 65% (575/883). Of these, 344 (59.8%) were EPA users and 231 (40.2%) were nonusers. Both groups indicated work burden as a barrier to implementation. Nonusers reported more barriers than users (mean [SD]: 7 [3.8] vs 5.8 [3.4], P < .001). Both groups identified training materials and premade assessment forms as facilitators to implementation. Users felt that EPAs were easier to understand than Milestones (89%) and better reflected what it meant to be a practicing subspecialty physician (90%). In contrast, nonusers felt that Milestones were easy to understand (57%) and reflected what it meant to be a practicing subspecialist (58%). CONCLUSIONS: Implementing EPA-based assessment will require a substantial investment by FPDs, facilitated by guidance and easily accessible resources provided by multiple organizations. Perceived barriers to be addressed include FPD time constraints, a need for additional assessment tools, and outcomes data.

Clinicogenomic characterization of inflammatory breast cancer.

Background: Inflammatory breast cancer (IBC) is a rare and poorly characterized type of breast cancer with an aggressive clinical presentation. The biological mechanisms driving the IBC phenotype are relatively undefined-partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts. Patients and Methods: A retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between clinically confirmed IBC cases within a dedicated IBC center versus non-IBC cases. Results: Clinicopathologic differences between IBC and non-IBC cases were consistent with prior reports-including IBC being associated with younger age at diagnosis, higher grade, and enrichment with hormone receptor (HR)-negative and HER2-positive tumors. The most frequent somatic alterations in IBC involved TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%) and GATA3 (8%). A multivariate logistic regression analysis revealed a significant enrichment in TP53 SNVs in IBC; particularly in HER2-positive and HR-positive disease which was associated with worse outcomes. Tumor mutational burden (TMB) did not differ substantially between IBC and non-IBC cases and a pathway analysis revealed an enrichment in NOTCH pathway alterations in HER2-positive disease. Conclusion: Taken together, this study provides a comprehensive, clinically informed landscape of somatic alterations in a large cohort of patients with IBC. Our data support higher frequency of TP53 mutations and a potential enrichment in NOTCH pathway activation-but overall; a lack of major genomic differences. These results both reinforce the importance of TP53 alterations in IBC pathogenesis as well as their influence on clinical outcomes; but also suggest additional analyses beyond somatic DNA-level changes are warranted.

The AMPK activator ATX-304 alters cellular metabolism to protect against cisplatin-induced acute kidney injury.

Acute kidney injury (AKI) disrupts energy metabolism. Targeting metabolism through AMP-activated protein kinase (AMPK) may alleviate AKI. ATX-304, a pan-AMPK activator, was evaluated in C57Bl/6 mice and tubular epithelial cell (TEC) cultures. Mice received ATX-304 (1 mg/g) or control chow for 7 days before cisplatin-induced AKI (CI-AKI). Primary cultures of tubular epithelial cells (TECs) were pre-treated with ATX-304 (20 µM, 4 h) prior to exposure to cisplatin (20 µM, 23 h). ATX-304 increased acetyl-CoA carboxylase phosphorylation, indicating AMPK activation. It protected against CI-AKI measured by serum creatinine (control 0.05 + 0.03 mM vs ATX-304 0.02 + 0.01 mM, P = 0.03), western blot for neutrophil gelatinase-associated lipocalin (NGAL) (control 3.3 + 1.8-fold vs ATX-304 1.2 + 0.55-fold, P = 0.002), and histological injury (control 3.5 + 0.59 vs ATX-304 2.7 + 0.74, P = 0.03). In TECs, pre-treatment with ATX-304 protected against cisplatin-mediated injury, as measured by lactate dehydrogenase release, MTS cell viability, and cleaved caspase 3 expression. ATX-304 protection against cisplatin was lost in AMPK-null murine embryonic fibroblasts. Metabolomic analysis in TECs revealed that ATX-304 (20 µM, 4 h) altered 66/126 metabolites, including fatty acids, tricarboxylic acid cycle metabolites, and amino acids. Metabolic studies of live cells using the XFe96 Seahorse analyzer revealed that ATX-304 increased the basal TEC oxygen consumption rate by 38%, whereas maximal respiration was unchanged. Thus, ATX-304 protects against cisplatin-mediated kidney injury via AMPK-dependent metabolic reprogramming, revealing a promising therapeutic strategy for AKI.

Ozanimod in Patients With Moderate to Severe Ulcerative Colitis Naive to Advanced Therapies.

BACKGROUND & AIMS: The pivotal phase 3 True North (TN) study demonstrated the efficacy and safety of ozanimod in patients with moderately to severely active ulcerative colitis. This analysis assessed ozanimod during TN and the ongoing open-label extension (OLE) in patients with active disease who were naive to advanced therapies (ATs). METHODS: TN was a randomized, double-blind, placebo-controlled trial consisting of 10-week induction period and 42-week maintenance period. Eligible patients could enter the OLE. Symptomatic efficacy was evaluated from induction through the OLE. Clinical, endoscopic, and mucosal outcomes were evaluated at the end of induction (Week [W] 10) and maintenance (W52) and at predefined OLE timepoints (OLE W46 and W94). Safety during TN was reported. RESULTS: This analysis included 616 AT-naive patients. Numerically greater proportions of patients receiving ozanimod than placebo achieved symptomatic response (39% vs 29%, 95% confidence interval, -0.1 to 18.8) by W2, with significant differences (56% vs 39%, 95% confidence interval, 6.3-26.3) achieved by W4. Patients receiving ozanimod showed significant improvements across efficacy outcomes versus placebo at W10 and W52 (P < .05, all endpoints). In patients on continuous ozanimod who entered the OLE in clinical response at W52, 91% maintained clinical response through OLE W94, and 74% achieved endoscopic improvement and 57% achieved mucosal healing at OLE W94. In ozanimod-treated patients without clinical response by W10 who received extended induction in the OLE, 62% achieved symptomatic response by OLE W10. Safety outcomes in AT-naive patients were consistent with the total TN population. CONCLUSIONS: Ozanimod is an effective, durable, and well-tolerated oral therapy for AT-naive ulcerative colitis patients. CLINICALTRIALS: gov, numbers NCT02435992 and NCT02531126.