Efficacy and Safety of Systemic Corticosteroids for Urticaria: A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Short courses of adjunctive systemic corticosteroids are commonly used to treat acute urticaria and chronic urticaria flares (both with or without mast cell-mediated angioedema), but their benefits and harms are unclear. OBJECTIVE: To evaluate the efficacy and safety of treating acute urticaria or chronic urticaria flares with versus without systemic corticosteroids. METHODS: We searched MEDLINE, EMBASE, CENTRAL, CNKI, VIP, Wanfang, and CBM databases from inception to July 8, 2023 for randomized controlled trials of treating urticaria with versus without systemic corticosteroids. Paired reviewers independently screened records, extracted data, and appraised risk of bias with the Cochrane 2.0 tool. We did random effects meta-analyses of urticaria activity, itch severity and adverse events. We assessed certainty of the evidence using the GRADE approach. RESULTS: We identified 12 randomized trials enrolling 944 patients. For patients with low or moderate probability (17.5% to 64%) to improve with antihistamines alone, add-on systemic corticosteroids likely improve urticaria activity by a 14% to 15% absolute difference (odds ratio [OR] 2.17, 95%CI 1.43-3.31; Number needed to treat [NNT] 7; Moderate certainty). Among patients with a high chance (95.8%) for urticaria to improve with antihistamines alone, add-on systemic corticosteroids likely improved urticaria activity by a 2.2% absolute difference (NNT, 45; Moderate certainty). Corticosteroids may improve itch severity (OR, 2.44; 95%CI 0.87-6.83; Risk difference, 9%; NNT, 11; Low certainty). Systemic corticosteroids also likely increase adverse events (OR, 2.76; 95%CI 1.00-7.62; Risk difference, 15%; number needed to harm [NNH], 9; Moderate certainty). CONCLUSION: Systemic corticosteroids for acute urticaria or chronic urticaria exacerbations likely improve urticaria, depending on antihistamine-responsiveness, but also likely increase adverse effects in approximately 15% more.

Differential Interactions of the Proteasome Inhibitor PI31 with Constitutive and Immuno-20S Proteasomes.

PI31 (Proteasome Inhibitor of 31,000 Da) is a 20S proteasome binding protein originally identified as an in vitro inhibitor of 20S proteasome proteolytic activity. Recently reported cryo-electron microscopy structures of 20S-PI31 complexes have revealed that the natively disordered proline-rich C-terminus of PI31 enters the central chamber in the interior of the 20S proteasome and interacts directly with the proteasome's multiple catalytic threonine residues in a manner predicted to inhibit their enzymatic function while evading its own proteolysis. Higher eukaryotes express an alternative form of the 20S proteasome (termed "immuno-proteasome") that features genetically and functionally distinct catalytic subunits. The effect of PI31 on immuno-proteasome function is unknown. We examine the relative inhibitory effects of PI31 on purified constitutive (20Sc) and immuno-(20Si) 20S proteasomes in vitro and show that PI31 inhibits 20Si hydrolytic activity to a significantly lesser degree than that of 20Sc. Unlike 20Sc, 20Si hydrolyzes the carboxyl-terminus of PI31 and this effect contributes to the reduced inhibitory activity of PI31 toward 20Si. Conversely, loss of 20Sc inhibition by PI31 point mutants leads to PI31 degradation by 20Sc. These results demonstrate unexpected differential interactions of PI31 with 20Sc and 20Si and document their functional consequences.

Cosmetic injectables in skin of color: A review of uses, safety, and effectiveness of neuromodulators and dermal fillers.

BACKGROUND: Skin of color (SOC) individuals represent a growing market for cosmetic injectables and can have different aesthetic goals and responses to treatment. OBJECTIVE: A review of the uses, safety, and effectiveness of injectable neuromodulators and dermal fillers in SOC individuals. METHODS AND MATERIALS: A search of the PubMed/MEDLINE database was conducted from August 1960 to December 2020. Studies that were included either had a focus on SOC (>20% SOC study participants) or dedicated article content commenting on the safety and/or efficacy of injectables in SOC participants. RESULTS: Of the 503 publications identified, a total of 88 articles were selected for this review. Differences in aging and cultural factors can influence aesthetic goals amongst SOC populations. Available data suggests that botulinum toxin (BTX) and dermal fillers are safe and effective in SOC populations, with the largest amount of data existing for Asian populations. There remains a paucity of research on Black and Latinx populations. CONCLUSION: BTX and dermal fillers are generally effective and well tolerated in SOC populations, particularly Asian populations for which the greatest amount of data exists. More high quality, randomized controlled trials in Black and Latinx populations are warranted.

Autophagy inhibition suppresses hormone production and cell growth in pituitary tumor cells: A potential approach to pituitary tumors.

Pituitary tumors (PTs) represent about 10% of all intracranial tumors, and most are benign. However, some PTs exhibit continued growth despite multimodal therapies. Although temozolomide (TMZ), an alkylating chemotherapeutic agent, is a first-line medical treatment for aggressive PTs, some PTs are resistant to TMZ. Existing literature indicated the involvement of autophagy in cell growth in several types of tumors, including PTs, and autophagy inhibitors have anti-tumor effects. In this study, the expression of several autophagy-inducible genes, including Atg3, Beclin1, Map1lc3A, Map1lc3b, Ulk1, Wipi2, and Tfe3 in two PT cell lines, the mouse corticotroph AtT-20 cells and the rat mammosomatotroph GH4 cells were identified. Down regulation of Tfe3, a master switch of basal autophagy, using RNA interference, suppressed cell proliferation in AtT-20 cells, suggesting basal autophagy contributes to the maintenance of cellular functions in PT cells. Expectedly, treatment with bafilomycin A1, an autophagy inhibitor, suppressed cell proliferation, increased the cleavage of PARP1, and reduced ACTH production in AtT-20 cells. Treatment with two additional autophagy inhibitors, chloroquine (CQ) and monensin, demonstrated similar effects on cell proliferation, apoptosis, and ACTH production in AtT-20 cells. Also, treatment with CQ suppressed cell proliferation and growth hormone production in GH4 cells. Moreover, the combination of CQ and TMZ had an additive effect on the inhibition of cell proliferation in AtT-20 and GH4 cells. The additive effect of anti-cancer drugs such as CQ alone or in combination with TMZ may represent a novel therapeutic approach for PTs, in particular tumors with resistance to TMZ.

Patterns of Access to Radiology Reports and Images Through a Patient Portal.

Access to radiology reports and images through a patient portal offers several advantages. The purpose of this study was to characterize patient's interactions with their radiology results. This was a retrospective study that evaluated radiography, ultrasound, computed tomography, magnetic resonance imaging, and positron emission tomography, exams performed between July 2020 and June 2021 for patients aged 12 and older. Exam information, access logs of radiology reports and images, and patient demographics were obtained from the electronic health record and image viewing software. Descriptive statistics were computed. The study included 1,685,239 exams. A total of 54.1% of reports were viewed. MRI and PET reports were viewed with the greatest frequency (70.2% and 67.6%, respectively); 25.5% of exam images were viewed, with the greatest frequency for MRI (40.1%). Exams were shared a total of 17,095 times and downloaded 8409 times; 64% of reports were viewed for patients aged 18-39 and 34% for patients aged 80 and greater. The rate of reports viewed was greater for patients with English as their preferred language (57.1%) compared to other languages (33.3%). Among those viewed, 56.5% of reports and 48.2% of images were viewed multiple times; 72.8% of images were viewed on smartphones, 25.8% on desktop computers, and 1.4% on tablets. Patients utilize a portal to view reports and view and share images. Continued efforts are warranted to promote the use of portals and create patient-friendly imaging results to help empower patients.

Identifying general reaction conditions by bandit optimization.

Reaction conditions that are generally applicable to a wide variety of substrates are highly desired, especially in the pharmaceutical and chemical industries1-6. Although many approaches are available to evaluate the general applicability of developed conditions, a universal approach to efficiently discover these conditions during optimizations is rare. Here we report the design, implementation and application of reinforcement learning bandit optimization models7-10 to identify generally applicable conditions by efficient condition sampling and evaluation of experimental feedback. Performance benchmarking on existing datasets statistically showed high accuracies for identifying general conditions, with up to 31% improvement over baselines that mimic state-of-the-art optimization approaches. A palladium-catalysed imidazole C-H arylation reaction, an aniline amide coupling reaction and a phenol alkylation reaction were investigated experimentally to evaluate use cases and functionalities of the bandit optimization model in practice. In all three cases, the reaction conditions that were most generally applicable yet not well studied for the respective reaction were identified after surveying less than 15% of the expert-designed reaction space.

Maternal and Fetal Radiation-Induced Cancer Risk From Computed Tomography Pulmonary Angiography During Pregnancy: A Retrospective Cohort Study Across a Multihospital Integrated Health Care Network.

OBJECTIVE: Computed tomography pulmonary angiogram (CTPA) is important to evaluate suspected pulmonary embolism in pregnancy but has maternal/fetal radiation risks. The objective of this study was to estimate maternal and fetal radiation-induced cancer risk from CTPA during pregnancy. METHODS: Simulation modeling via the National Cancer Institute's Radiation Risk Assessment Tool was used to estimate excess cancer risks from 17 organ doses from CTPA during pregnancy, with doses determined by a radiation dose indexing monitoring system. Organ doses were obtained from a radiation dose indexing monitoring system. Maternal and fetal cancer risks per 100,000 were calculated for male and female fetuses and several maternal ages. RESULTS: The 534 CTPA examinations had top 3 maternal organ doses to the breast, lung, and stomach of 17.34, 15.53, and 9.43 mSv, respectively, with a mean uterine dose of 0.21 mSv. The total maternal excess risks of developing cancer per 100,000 were 181, 151, 121, 107, 94.5, 84, and 74.4, respectively, for a 20-, 25-, 30-, 35-, 40-, 45-, and 50-year-old woman undergoing CTPA, compared with baseline cancer risks of 41,408 for 20-year-old patients. The total fetal excess risks of developing cancer per 100,000 were 12.3 and 7.3 for female and male fetuses, respectively, when compared with baseline cancer risks of 41,227 and 48,291. DISCUSSION: Excess risk of developing cancer from CTPA was small relative to baseline cancer risk for pregnant patients and fetuses, decreased for pregnant patients with increasing maternal age, and was greater for female fetuses than male fetuses.

Mimicking Protein Kinase C Phosphorylation Inhibits Arc/Arg3.1 Palmitoylation and Its Interaction with Nucleic Acids.

Activity-regulated cytoskeleton-associated protein (Arc) plays essential roles in diverse forms of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), and homeostatic plasticity. In addition, it assembles into virus-like particles that may deliver mRNAs and/or other cargo between neurons and neighboring cells. Considering this broad range of activities, it is not surprising that Arc is subject to regulation by multiple types of post-translational modification, including phosphorylation, palmitoylation, SUMOylation, ubiquitylation, and acetylation. Here we explore the potential regulatory role of Arc phosphorylation by protein kinase C (PKC), which occurs on serines 84 and 90 within an α-helical segment in the N-terminal domain. To mimic the effect of PKC phosphorylation, we mutated the two serines to negatively charged glutamic acid. A consequence of introducing these phosphomimetic mutations is the almost complete inhibition of Arc palmitoylation, which occurs on nearby cysteines and contributes to synaptic weakening. The mutations also inhibit the binding of nucleic acids and destabilize high-order Arc oligomers. Thus, PKC phosphorylation of Arc may limit the full expression of LTD and may suppress the interneuronal transport of mRNAs.

Simplified homology-assisted CRISPR for gene editing in Drosophila.

In vivo genome editing with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 generates powerful tools to study gene regulation and function. We revised the homology-assisted CRISPR knock-in method to convert Drosophila GAL4 lines to LexA lines using a new universal knock-in donor strain. A balancer chromosome-linked donor strain with both body color (yellow) and eye red fluorescent protein (RFP) expression markers simplified the identification of LexA knock-in using light or fluorescence microscopy. A second balancer chromosome-linked donor strain readily converted the second chromosome-linked GAL4 lines regardless of target location in the cis-chromosome but showed limited success for the third chromosome-linked GAL4 lines. We observed a consistent and robust expression of the yellow transgene in progeny harboring a LexA knock-in at diverse genomic locations. Unexpectedly, the expression of the 3xP3-RFP transgene in the "dual transgene" cassette was significantly increased compared with that of the original single 3xP3-RFP transgene cassette in all tested genomic locations. Using this improved screening approach, we generated 16 novel LexA lines; tissue expression by the derived LexA and originating GAL4 lines was similar or indistinguishable. In collaboration with 2 secondary school classes, we also established a systematic workflow to generate a collection of LexA lines from frequently used GAL4 lines.

Ten-Year Trend in Advanced Imaging Utilization for Suspected Pulmonary Embolism in Pregnancy.

PURPOSE: Advanced imaging is essential to diagnose pulmonary embolism (PE) in pregnancy, but there are associated maternal and fetal radiation risks. The purpose of this study was to evaluate the 10-year trend in advanced imaging utilization for the evaluation of suspected PE in pregnancy. METHODS: The authors evaluated pregnant women with advanced imaging using CT pulmonary angiography (CTPA) or lung scintigraphy (LS) for evaluation of suspected PE presenting to two tertiary hospitals from 2007 to 2016. The rate of imaging was evaluated relative to positive PE rate and local pregnancy rate. positive PE was defined as a new acute PE finding on any advanced imaging within 3 days of first advanced imaging test. Local pregnancy rates were defined per 1,000 pregnancies in the county serviced by both hospitals. Chi-square testing was used to evaluate statistical significance (P < .05) in the utilization trend of advanced imaging and relative to local pregnancy rates and evaluations positive for PE. RESULTS: A total of 707 pregnant patients were identified, of whom 92.5% (n = 654) underwent CTPA and 7.5% (n = 53) underwent LS. Regression analysis showed an average increase of 5.2 advanced imaging studies per year (P < .001), with 61 and 105 studies performed in 2007 and 2016, respectively. Additionally, there was an average increase of 0.08 (P < .001) advanced imaging studies per 1,000 local pregnancies per year, doubling from 0.7 in 2007 to 1.4 in 2016 (P < .001). Finally, there was a decrease of 0.004 (P = .009) in advanced imaging positive for PE, from 3% (2 of 61) in 2007 to 0% (0 of 100) in 2016. CONCLUSIONS: Advanced imaging utilization increased by 72% over the 10-year window, driven by higher use of CTPA. Although the detection rate of PE on advanced imaging has decreased, the utilization rate among pregnant patients doubled during this period. These results highlight the need to consider the radiation risks and costs of advanced imaging in specific patient populations.

Acute ischemic stroke outcomes in patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Although patients with COVID-19 have a higher risk of acute ischemic stroke (AIS), the impact on stroke outcomes remains uncertain. AIMS: To determine the clinical outcomes of patients with AIS and COVID-19 (AIS-COVID+). METHODS: We performed a systematic review and meta-analysis following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Our protocol was registered with the International Prospective Register of Systematic Reviews (CRD42020211977). Systematic searches were last performed on June 3, 2021 in EMBASE, PubMed, Web-of-Science, Scopus, and CINAHL Databases. INCLUSION CRITERIA: (1) studies reporting outcomes on AIS-COVID+; (2) original articles published in 2020 or later; (3) study participants aged ≥18 years. EXCLUSION CRITERIA: (1) case reports with <5 patients, abstracts, review articles; (2) studies analyzing novel interventions. Risk of bias was assessed using the Mixed Methods Appraisal Tool. Random-effects models estimated the pooled OR and 95% confidence intervals (95% CI) for mortality, modified Rankin Scale (mRS) score, length of stay (LOS), and discharge disposition. RESULTS: Of the 43 selected studies, 46.5% (20/43) reported patients with AIS without COVID-19 (AIS-COVID-) for comparison. Random-effects model included 7294 AIS-COVID+ and 158 401 AIS-COVID-. Compared with AIS-COVID-, AIS-COVID+ patients had higher in-hospital mortality (OR=3.87 (95% CI 2.75 to 5.45), P<0.001), less mRS scores 0-2 (OR=0.53 (95% CI 0.46 to 0.62), P<0.001), longer LOS (mean difference=4.21 days (95% CI 1.96 to 6.47), P<0.001), and less home discharge (OR=0.31 (95% CI 0.21 to 0.47), P<0.001). CONCLUSIONS: Patients with AIS-COVID had worse outcomes, with almost fourfold increased mortality, half the odds of mRS scores 0-2, and one-third the odds of home discharge. These findings confirm the significant impact of COVID-19 on early stroke outcomes.

Gender-Based Disparity in Acute Stroke Imaging Utilization and the Impact on Treatment and Outcomes: 2012 to 2021.

INTRODUCTION: Prior studies have revealed significant socio-economic disparities in neuro-imaging and treatment utilization for patients with acute ischemic stroke (AIS). In this study, we sought to evaluate whether a sex-based disparity exists in neuro-imaging and to determine its etiology and association with acute treatment and outcomes. MATERIALS AND METHODS: This was a retrospective study of consecutive patients with AIS admitted to a comprehensive stroke center between 2012 and 2021. Patient demographic and clinical characteristics, neuro-imaging, acute treatment, and early clinical outcomes were extracted from the electronic medical records. Trend analysis, bivariate analysis of patient characteristics by sex, and multivariable logistic regression analyses were conducted. RESULTS: Of the 7,540 AIS episodes registered from 2012 to 2021, 47.9% were female patients. After adjusting for demographic, clinical, and temporal factors, significantly higher utilization of CTA was found for male patients (odds ratio = 1.20 [95% confidence interval 1.07-1.34]), particularly from socio-economically advantaged groups, and in years 2015 and 2019, representing the years endovascular thrombectomy recommendations changed. Despite this, male patients had significantly lower intravenous thrombolysis utilization (odds ratio = 0.83 [95% confidence interval 0.71-0.96]) and similar endovascular thrombectomy rates as female patients. There were no significant sex differences in early clinical outcomes, and no relevant clinical or demographic factors explained the CT angiography utilization disparity. CONCLUSION: Despite higher CT angiography utilization in socio-economically advantaged male patients with AIS, likely overutilization due to implicit biases following guideline updates, the rates of acute treatment, and early clinical outcomes were unaffected.

Barriers to blockchain adoption in the seaport industry: A fuzzy DEMATEL analysis.

Blockchain technology, marked as a disruptive force across various sectors, including seaport logistics, faces challenges and obstacles that impede its effective adoption. We aim to empirically identify the significant barriers impeding blockchain adoption in the seaport industry and elucidate the interconnected relationships between these impediments. Utilizing the Fuzzy Decision-Making Trial and Evaluation Laboratory Analysis (Fuzzy DEMATEL) technique, we quantify the cause-and-effect relationships between various barriers to blockchain adoption. Structured interviews involving 18 experts were conducted, collecting both qualitative interview data and quantitative data. The nature of ports and the maritime industry did not seem to be accurately reflected in the literature about blockchain adoption, presenting several new findings in this study. Four primary obstacles were identified: 1) Lack of management support and commitment. 2) Issues in supply chain collaboration, communication and coordination. 3) Resistance from and lack of involvement of external stakeholders. 4) The high cost. Furthermore, cost was reaffirmed as a significant factor influencing blockchain adoption. We enhance existing literature by revealing the interdependencies among identified barriers and offers insights for policymakers and industry practitioners. We aim to foster successful blockchain integration in the seaport industry, improving its sustainability performance. During this research, it has been acknowledged by the business sector that the effective employment of business process re-engineering (BPR) and the strategic implementation of blockchain technology are crucial strategies to surmount the obstacles that have impeded the extensive integration of blockchain within port operations.

Novel signatures of prostate cancer progression and therapeutic resistance.

INTRODUCTION: The extensive heterogeneity of prostate cancer (PCa) and multilayered complexity of progression to castration-resistant prostate cancer (CRPC) have contributed to the challenges of accurately monitoring advanced disease. Profiling of the tumor microenvironment with large-scale transcriptomic studies have identified gene signatures that predict biochemical recurrence, lymph node invasion, metastases, and development of therapeutic resistance through critical determinants driving CRPC. AREAS COVERED: This review encompasses understanding of the role of different molecular determinants of PCa progression to lethal disease including the phenotypic dynamic of cell plasticity, EMT-MET interconversion, and signaling-pathways driving PCa cells to advance and metastasize. The value of liquid biopsies encompassing circulating tumor cells and extracellular vesicles to detect disease progression and emergence of therapeutic resistance in patients progressing to lethal disease is discussed. Relevant literature was added from PubMed portal. EXPERT OPINION: Despite progress in the tumor-targeted therapeutics and biomarker discovery, distant metastasis and therapeutic resistance remain the major cause of mortality in patients with advanced CRPC. No single signature can encompass the tremendous phenotypic and genomic heterogeneity of PCa, but rather multi-threaded omics-derived and phenotypic markers tailored and validated into a multimodal signature.

Botfly myiasis after travel to Bolivia.

Following a trip to Bolivia, a 32-year-old woman developed a left lower leg ulcer with a sensation of movement within the lesion. After being seen by four primary care providers, she was referred to dermatology 7 weeks after her return from Bolivia. At that time, she was found to have a 5 mm weeping ulcer, with a live larva visible at the base. We conducted a punch biopsy for botfly removal, after which the patient healed well. Herein we discuss the ways in which clinical presentation, history of travel, dermoscopy, and ultrasound can contribute to diagnosing botfly myiasis. While treatment of botfly infestation is not required, we discuss the importance of shared decision-making in considering treatment, as well as methods for extraction, including mechanical or surgical removal, which may help to reduce patient anxiety and the risk for secondary infection. As global travel resumes to levels prior to the Covid-19 pandemic, it is important for dermatologists to be aware of the presenting symptoms and treatment of tropical skin disorders.

Systemic treatments for atopic dermatitis (eczema): Systematic review and network meta-analysis of randomized trials.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes. OBJECTIVE: We sought to systematically synthesize the benefits and harms of AD systemic treatments. METHODS: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT databases from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. This review is registered in the Open Science Framework (https://osf.io/e5sna). RESULTS: The 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty evidence, high-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for 2 outcomes. These Janus kinase inhibitors were among the most harmful in increasing adverse events. With high-certainty evidence, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest, modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. Efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain. CONCLUSIONS: Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes, but also is among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and have favorable safety.

Aggregation of Size-Selected Oxide Clusters Deposited onto Au(111).

Kinetic Monte Carlo (kMC) simulations along with density functional theory (DFT) calculations were used to investigate the aggregation of size-selected Nb3Oy (y = 5, 6, 7) clusters deposited onto the Au(111) surface. Recent STM experiments showed that the cluster binding sites and sizes of the cluster assemblies on the Nb3Oy/Au(111) surfaces strongly depend on the stoichiometry of the clusters, i.e., the oxygen-to-niobium ratio. To better understand the origins of these differences, kMC simulations of the nucleation and growth of cluster assemblies were performed using energy barriers for diffusion and intercluster interactions estimated from DFT calculations of cluster binding and dimerization energies, respectively. Comparisons of the kMC simulations with STM images of the as-deposited Nb3Oy/Au(111) surfaces at RT and after high temperature annealing were used to further optimize the energetics and gauge the importance of nearest neighbor interactions. The kMC simulations demonstrate that the assembly of Nb3Oy clusters on Au(111) are largely controlled by the magnitude of the barriers for diffusion and interparticle-bond formation, while changes at higher temperatures are sensitive to the binding energies between nearest neighbors. Simulations for the Nb3O5 and Nb3O6 clusters, which exhibit smaller cluster assembly sizes in STM, required larger diffusion barriers as well as different barriers for interparticle binding, which reflected differences in DFT calculated dimerization energies. The results demonstrate the effectiveness of combined DFT and kMC calculations for understanding how the stoichiometry affects the aggregation of small oxide clusters on a metal surface.

Operational prediction of solar flares using a transformer-based framework.

Solar flares are explosions on the Sun. They happen when energy stored in magnetic fields around solar active regions (ARs) is suddenly released. Solar flares and accompanied coronal mass ejections are sources of space weather, which negatively affects a variety of technologies at or near Earth, ranging from blocking high-frequency radio waves used for radio communication to degrading power grid operations. Monitoring and providing early and accurate prediction of solar flares is therefore crucial for preparedness and disaster risk management. In this article, we present a transformer-based framework, named SolarFlareNet, for predicting whether an AR would produce a [Formula: see text]-class flare within the next 24 to 72 h. We consider three [Formula: see text] classes, namely the [Formula: see text]M5.0 class, the [Formula: see text]M class and the [Formula: see text]C class, and build three transformers separately, each corresponding to a [Formula: see text] class. Each transformer is used to make predictions of its corresponding [Formula: see text]-class flares. The crux of our approach is to model data samples in an AR as time series and to use transformers to capture the temporal dynamics of the data samples. Each data sample consists of magnetic parameters taken from Space-weather HMI Active Region Patches (SHARP) and related data products. We survey flare events that occurred from May 2010 to December 2022 using the Geostationary Operational Environmental Satellite X-ray flare catalogs provided by the National Centers for Environmental Information (NCEI), and build a database of flares with identified ARs in the NCEI flare catalogs. This flare database is used to construct labels of the data samples suitable for machine learning. We further extend the deterministic approach to a calibration-based probabilistic forecasting method. The SolarFlareNet system is fully operational and is capable of making near real-time predictions of solar flares on the Web.

Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody-Drug Conjugate for the Treatment of Cancer.

Antibody-drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well as the number of payload drugs per antibody [drug-to-antibody ratio (DAR)]. To allow for ADC optimization for a given target antigen, we developed Dolasynthen (DS), a novel ADC platform based on the payload auristatin hydroxypropylamide, that enables precise DAR-ranging and site-specific conjugation. We used the new platform to optimize an ADC that targets B7-H4 (VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660 is a site-specific DS DAR 6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory to PD-1 immune checkpoint inhibition. In a panel of 28 breast cancer PDXs, XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a phase I study (NCT05377996) in patients with cancer.