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Adjuvant Atezolizumab for Early Triple-Negative Breast Cancer The ALEXANDRA/IMpassion030 Randomized Clinical Trial
No full textIMPORTANCE Triple-negative breast cancer is an aggressive subtype with a high incidence in young patients, a high incidence in non-Hispanic Black women, and a high risk of progression to metastatic cancer, a devastating sequela with a 12- to 18-month life expectancy. Until recently, one strategy for treating early-stage triple-negative breast cancer was chemotherapy after surgery. However, it was not known whether the addition of immune therapy to postsurgery chemotherapy would be beneficial. OBJECTIVE To evaluate the addition of immune therapy in the form of atezolizumab to postoperative chemotherapy in patients with the high-risk triple-negative breast cancer subtype. DESIGN, SETTING, AND PARTICIPANTS In this open-label international randomized phase 3 trial conducted in more than 330 centers in 31 countries, patients undergoing surgery as initial treatment for stage II or III triple-negative breast cancer were enrolled between August 2, 2018, and November 11, 2022. The last patient follow-up was on August 18, 2023. INTERVENTIONS Patients were randomized (1:1) to receive standard chemotherapy for 20 weeks with (n = 1101) or without (n =1098) the immune therapy drug atezolizumab for up to 1 year. MAIN OUTCOMES AND MEASURES The primary end point was invasive disease-free survival (time between randomization and invasive breast cancer in the same or opposite breast, recurrence elsewhere in the body, or death from any cause). RESULTS The median age of enrolled patients was 53 years and most self-reported as being of Asian or White race and neither Latino nor Hispanic ethnicity. The study independent data monitoring committee halted enrollment at 2199 of 2300 planned patients. All patients stopped atezolizumab followinga planned early interim and futility analysis. The trial continued to a premature final analysis. With invasive disease-free survival events in 141 patients (12.8%) treated with atezolizumab-chemotherapy and 125 (11.4%) with chemotherapy alone (median follow-up, 32 months), the final stratified invasive disease-free survival hazard ratio was 1.11(95% CI, 0.87-1.42; P = .38). Compared with chemotherapy alone, the regimen of atezolizumab plus chemotherapy was associated with more treatment-related grade 3 or 4 adverse events (54% vs 44%) but similar incidences of fatal adverse events (0.8% vs 0.6%) and adverse events leading to chemotherapy discontinuation. Chemotherapy exposure was similar in the 2 treatment groups. CONCLUSIONS AND RELEVANCE The addition of the immune therapy drug atezolizumab to chemotherapy after surgery did not provide benefit among patients with triple-negative breast cancer who are at high risk of recurrent disease.N
Tailoring formulation for enhanced phage therapy in canine otitis externa: a cocktail approach targeting Pseudomonas aeruginosa and Staphylococcus pseudintermedius
No full textCanine otitis externa, characterized by the involvement of diverse bacterial species, notably Pseudomonas aeruginosa and Staphylococcus pseudintermedius, necessitates antibiotic administration as the primary therapeutic approach; however, prolonged treatment often precipitates antibiotic resistance. Therefore, the application of bacteriophages as antimicrobial agents has been of interest recently. However, phage therapy has limitations; its efficacy depends on the lytic capacity of the phage and the emergence of phage resistance, which can be overcome by using phage cocktails. This study aimed to enhance the therapeutic potential of bacteriophages by supplementing additional materials to hinder the pathogens and combining different viruses to broaden the lytic spectrum. The therapeutic potential of the phage cocktail, consisting of Pseudomonas phage pPa_SNUABM_DT01 and Staphylococcus phage pSp_SNUABM-J, was evaluated using an in vitro planktonic bacterial cell lysis assay and a biofilm degradation assay. Additionally, its efficacy was assessed using an in vivo mouse otitis externa model and clinical administration in five dogs with chronic Pseudomonas aeruginosa and Staphylococcus pseudintermedius otitis externa. The phage cocktail with formulation, including glycerol, glycine, and Tween 20, as additional components resulted in a significant reduction in bacterial counts and clinical improvements, including odor, discharge type and amount, and inflammatory symptoms. The results suggest that administering a phage cocktail solution with additional components could make phage therapy a more efficient treatment for otitis externa in dogs. This offers a practical alternative to traditional antibiotic treatments and could help mitigate antibiotic resistance in veterinary medicine.N
Real-Time Detection of Sub-ppm Aromatic Compounds in Alcohol by Surface Plasmon Resonance Using Label-Free Graphene
No full textThe increasing importance of high-purity isopropyl alcohol (IPA) in semiconductor processing technology has led to a higher demand for technologies capable of detecting impurities in IPA. Although accurate and various impurity detection technologies have been developed, most of them have limitations in real-time and repeatable detection of impurities. Herein, for the first time, surface plasmon resonance (SPR) sensor was developed utilizing graphene transferred Au film (Au/graphene) to detect sub-ppm levels of 2,4-dinitrophenol (2,4-DNP) dissolved in IPA and this sensor demonstrates the ability to detect 2,4-DNP in real-time with great reversibility. The adsorption of 2,4-DNP to graphene is found to be stronger than that for Au film because of noncovalent graphene pi-pi stacking interaction, and the effect of graphene is demonstrated through density function theory (DFT) calculations and enhancement in sensing performance of Au/graphene sensor. Additionally, the presence of noncovalent pi-pi stacking interaction between 2,4-DNP and graphene has been demonstrated by confirming the p-doping effect of graphene-based solution field-effect transistor measurements and consecutive Raman spectra analysis. This study offers experimental and theoretical insights into the adsorption kinetics of 2,4-DNP dissolved in IPA and provides promising perspectives for real-time sensing technology utilizing label-free graphene to detect impurities in high-purity cleaning agents.Y
Clean energy supply and demand strategies of Jeju Island to achieve carbon net-zero by using digital twin technology
No full textJeju Island, the largest island in South Korea with abundant renewable resources, aims to meet 100 % of its 2030 power demand with renewable energy. However, controlling the fluctuation of renewable energy is challenging due to the lack of appropriate energy distribution strategies. Herein, we report the new supply and demand management hybrid system on an island scale through battery energy storage system (BESS), plus demand response (DR), high voltage direct current (HVDC) transmission system, and power-to-H2 gas (P2G) technology. According to the digital twin simulation, the most important system over the 25 years starting from 2030 is HVDC#1 reverse transmission. Compared to the base scenario based on the current system, optimized scenario 4 (incentive $0.6, after P2G) showed the reduction in excess energy to 27.08 % of the base scenario. Sensitivity analysis showed that to meet the predicted hydrogen price for 2030, the P2G efficiency should be increased to 82.1 %, and installing P2G facilities without limitations can eliminate all excess energy with an NPC increase of 13.4 % compared to the base scenario. Therefore, this paper proves that (1) enabling reverse transmission of HVDC#1 in the short term and (2) increasing P2G efficiency and capacity in the long term are crucial.N
TTD: Text-Tag Self-Distillation Enhancing Image-Text Alignment in CLIP to Alleviate Single Tag Bias
No full textWe identify a critical bias in contemporary CLIP-based models, which we denote as single tag bias. This bias manifests as a disproportionate focus on a singular tag (word) while neglecting other pertinent tags, stemming from CLIP embeddings prioritizing one specific tag in image-text relationships. In this paper, we introduce a novel two-step fine-tuning approach, Text-Tag Self-Distillation (TTD), to address this challenge. We first extract all image-relevant tags from text based on their similarity to the nearest pixels. Then, we distill a combined mask containing the extracted tags' content to a text-derived mask. This approach ensures the unbiased image-text alignment of the CLIP-based models using only image-text pairs without necessitating additional supervision. Our technique demonstrates model-agnostic improvements in multitag classification and segmentation tasks, surpassing competing methods that rely on external resources. The code and data are available at https://github.com/shjo-april/TTD.N
The biogenesis and regulation of animal microRNAs
No full textMicroRNAs (miRNAs) are small, yet profoundly influential, non-coding RNAs that base-pair with mRNAs to induce RNA silencing. Although the basic principles of miRNA biogenesis and function have been established, recent breakthroughs have yielded important new insights into the molecular mechanisms of miRNA biogenesis. In this Review, we discuss the metazoan miRNA biogenesis pathway step-by-step, focusing on the key biogenesis machinery, including the Drosha-DGCR8 complex (Microprocessor), exportin-5, Dicer and Argonaute. We also highlight newly identified cis-acting elements and their impact on miRNA maturation, informed by advanced high-throughput and structural studies, and discuss recently discovered mechanisms of clustered miRNA processing, target recognition and target-directed miRNA decay (TDMD). Lastly, we explore multiple regulatory layers of miRNA biogenesis, mediated by RNA-protein interactions, miRNA tailing (uridylation or adenylation) and RNA modifications.N
A Systematic Review and Narrative Synthesis of Strategies for Disaster Risk Reduction Education for People With Disabilities
No full textAimsTo identify the components and characteristics of disaster risk reduction education for people with disabilities and to explore the contents and results of disaster risk reduction education.DesignA systematic review and narrative synthesis.Review MethodsThe review was conducted in accordance with Tawfik's guidelines and followed the reporting standards outlined in the Preferred Reporting Items for Systematic reviews and Meta-Analysis. The quality appraisal was guided by the mixed methods appraisal tool. The contents of each type of education were narratively synthesised.Data SourcesThe literature search was conducted in December 2023 using several electronic databases, including PubMed, EMBASE, CINAHL, Cochrane library and PsycINFO.ResultsEight quantitative studies were selected for this study. Disaster risk reduction education for people with disabilities has focused mainly on fires and earthquakes, and drills were the most used teaching method. Some of the education was conducted by designating a 1:1 ratio of educators and participants or modifying the ratio according to the type of disability. The staff mainly conducted the education, and after education, the effect of disaster risk reduction education was confirmed in terms of the knowledge and response of people with disabilities during drills.ConclusionThis review provides insights for developing disaster risk reduction education for people with disabilities. However, only a few randomised controlled trial (RCT) studies and quasi-experimental studies have been conducted, and several studies have bias risks. Thus, practical, continuous, quality interventions are needed for effective disaster risk reduction education for people with disabilities.ImpactThis systematic review analysed the research trends of disaster risk reduction education for people with disabilities. The results provide the basis for quality evaluations of the operation, methods and achievements of educational programmes. Efforts are needed to promote collaboration between researcher and the practitioners to conduct further quality research.Patient or Public ContributionNo Patient or Public Contribution: Systematic review.N
Attribution of 2022 August Heavy Precipitation Event in South Korea Using High-Resolution Pseudo Global Warming Simulations: Sensitivity to Vertical Temperature Changes
No full textThis study examines the anthropogenic influences on the heavy precipitation event that occurred in early August 2022, South Korea, using a pseudo global warming (PGW) method with a convection-permitting model. Pseudo global warming experiments for counterfactual natural non-warming conditions (NAT) were conducted by removing anthropogenic warming patterns from the observations. The anthropogenic warming patterns were estimated from the differences between Coupled Model Inter-comparison Project Phase 6 historical and historical natural-only simulations. Two NAT experiments were performed by using the multi-model mean of all nine models (NATT) and the three models with weaker upper tropospheric warming (NATW). The results show that atmospheric moisture is reduced in both NAT experiments compared to the current-condition experiments, but that enhanced convective instability due to upper tropospheric cooling offsets the effect of moisture reduction, resulting in similar precipitation responses. This compensation effect becomes weak in NATW, indicating the important role of the vertical profile of anthropogenic warming pattern in PGW-based attribution experiments.Y
Clinical outcome and volumetric 3D analysis of biofluorescence imaging system guided surgery for Medication-Related Osteonecrosis of the Jaw(MRONJ)
No full textBackgroundThis study aims to evaluate the clinical outcome of biofluorescent imaging system (BIS) guided MRONJ surgery through analyzing 3D volumetric changes in CBCT data of bone structure.MethodsBIS-guided surgery for MRONJ surgery was performed by grinding red-fluorescent area from remained residual bone detected by Qray-pen. CBCT data was collected preoperatively, postoperatively, and at last follow-up more than 3 months of each patient. Healing ratio per month was calculated through measuring difference between postoperative defect and last follow-up defect volume by analyzing CBCT.ResultsWith mean follow-up period of 7.8 +/- 4.8 months, twelve MRONJ surgeries of 11 patients (2 males, 9 females, mean 72.8 +/- 13.7 years old) showed bone healing tendency without recurrence in average healing ratio of 5.49 +/- 2.22% per month, with complete soft tissue closure. It was observed that the healing ratio per month did not show statistically significant differences based on location of MRONJ, size of post-operative defect volume, nor duration of bisphosphonate intake before surgery.ConclusionsBased on three-dimensional bone analysis, efficacy of BIS-based MRONJ surgery was proved through the recovery pattern of underlying bone structure and no recurrence sign showing.Clinical trial registrationNot applicable.Y
Investigational Use of Real-World Data as a Hybrid Control in Pancreatic Ductal Adenocarcinoma from the Randomized Phase Ib/II MORPHEUS Trial
No full textEnrolling adequate numbers of patients into the control arm of randomized controlled trials (RCTs) often presents barriers. There is interest in leveraging real-world data (RWD) from electronic health records (EHRs) to construct external control (EC) arms to supplement RCT control arms and form hybrid control (HC) arms. This investigation showed the use of an HC arm in second-line metastatic pancreatic ductal adenocarcinoma (PDAC). The RCT experimental arm (atezolizumab + PEGylated recombinant human hyaluronidase (Atezo + PEGPH20)) was compared with an HC arm consisting of patients treated with modified FOLFOX6 or gemcitabine/nab-paclitaxel from the MORPHEUS PDAC internal control arm supplemented with data from a nationwide EHR-derived de-identified database as the EC arm. The EC arm was constructed by applying key inclusion/exclusion criteria from the MORPHEUS PDAC trial to patients from the real-world cohort. Baseline variables were balanced using propensity score matching and covariate adjustment. Three analysis approaches-Cox model with pooled-control data, Cox model with control arm-specific frailty, and Bayesian analysis using a commensurate prior-were assessed. Overall survival was similar between the treatment arms. The direction and magnitude of hazard ratios (HRs) from the multiple HC analyses (HRs ranged from 1.02 to 1.06) were comparable with the reported trial HR (HR 0.91; 95% CI: 0.56, 1.49). This analysis demonstrates the feasibility and applicability of leveraging RWD in clinical trial design to supplement clinical trial control arms.Y