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Measuring SARS-CoV-2 RNA in Bangkok wastewater treatment plants and estimating infected population after fully opening the country in 2023, Thailand
Phase II Trial of Risk-Enabled Therapy After Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer (RETAIN 1)
PURPOSE Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Mutations in DNA damage repair genes are associated with pathologic downstaging after NAC. We hypothesized that a combination of biomarker selection and clinical staging would identify patients for cystectomy-sparing active surveillance (AS). PATIENTS AND METHODS We conducted a single-arm, phase II, noninferiority trial to evaluate a risk-adapted approach for MIBC. Patients with cT2-T3N0M0 MIBC underwent NAC with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC). Pre-NAC transurethral bladder tumor specimens were sequenced for mutations in ATM , ERCC2 , FANCC , and RB1 . Patients with ≥1 mutation and cT0 post-NAC began AS. The primary end point was metastasis-free survival (MFS) at 2 years for the entire cohort with the null hypothesis rejected if the lower bound exact one-sided 95% CI exceeds 64%. RESULTS Seventy patients were enrolled, 33 (47%) had a mutation, and 25 (36%) began per-protocol AS. With a median follow-up of 40 months, the 2-year MFS for all patients was 72.9% (lower bound exact one-sided 95% CI, 62.8). The 2-year MFS was 76.0% in the AS group (95% CI, 54.2 to 88.4) and 71.1% (95% CI, 55.5 to 82.1) in the remaining patients. In the AS group, 17 patients (68%) had some recurrence and 12 (48%) were metastasis-free with an intact bladder. The 2-year overall survival (OS) was 84.3% (95% CI, 73.4 to 91.0); OS was 88.0% (95% CI, 67.3 to 96.0) and 82.2% (95% CI, 67.6 to 90.7) in the AS and not-AS groups, respectively. CONCLUSION Patients with MIBC treated with AMVAC followed by a risk-adapted approach to local consolidation achieved a 2-year MFS rate of 73%. The primary end point was not met, but 17% of all enrolled patients and 48% of the AS group avoided cystectomy without metastatic disease.
Publisher Correction: FRET analysis of the unwrapping of nucleosomal DNA containing a sequence characteristic of the + 1 nucleosome
Expanding the Horizon of MRONJ Research in Breast Cancer Bone Metastasis Treatments
Biochemical and physiological characterization of Aedes aegypti midgut chymotrypsin
Abemaciclib Plus Fulvestrant in Advanced Breast Cancer After Progression on CDK4/6 Inhibition: Results From the Phase III postMONARCH Trial
PURPOSE Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the standard first-line treatment for hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC); however, disease progression occurs in almost all patients and additional treatment options are needed. Herein, we report outcomes of the postMONARCH trial investigating a switch in ET with/without CDK4/6 inhibition with abemaciclib after disease progression on CDK4/6i. METHODS This double-blind, randomized phase III study enrolled patients with disease progression on previous CDK4/6i plus aromatase inhibitor as initial therapy for advanced disease or recurrence on/after adjuvant CDK4/6i + ET. Patients were randomly assigned (1:1) to abemaciclib + fulvestrant or placebo + fulvestrant. The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included PFS by blinded independent central review, objective response rate (ORR), and safety. RESULTS This study randomly assigned 368 patients (abemaciclib + fulvestrant, n = 182 placebo + fulvestrant, n = 186). At the primary analysis (258 events), the hazard ratio (HR) was 0.73 (95% CI, 0.57 to 0.95; nominal P = .017), with median PFS 6.0 (95% CI, 5.6 to 8.6) versus 5.3 (95% CI, 3.7 to 5.6) months and 6-month PFS rates of 50% and 37% in the abemaciclib + fulvestrant and placebo + fulvestrant arms, respectively. These results were supported by BICR-assessed PFS (HR, 0.55 [95% CI, 0.39 to 0.77]; nominal P < .001). A consistent treatment effect was seen across major clinical and genomic subgroups, including with/without ESR1 or PIK3CA mutations. Among patients with measurable disease, investigator-assessed ORR was improved with abemaciclib + fulvestrant versus placebo + fulvestrant (17% v 7%; nominal P = .015). No new safety signals were observed, with findings consistent with the known safety profile of abemaciclib. CONCLUSION Abemaciclib + fulvestrant significantly improved PFS after disease progression on previous CDK4/6i + ET in patients with HR+, HER2– ABC, offering an additional targeted therapy option for these patients.
Incorporation of biochar and semi-interpenetrating biopolymer to synthesize new slow release fertilizers and their impact on soil moisture and nutrients availability
Reply to: Adjuvant Chemotherapy on Resected Intraductal Papillary Mucinous Neoplasm–Derived Pancreatic Cancer: Addressing Statistical and Methodological Concerns in Survival Analysis
A 180 nm CMOS dual-mode LNA with current reuse and double-resonance load for 2.4 GHz and 3.1–10.6 GHz wireless communication
Evaluation and Surgical Management of Pediatric Cutaneous Melanoma and Atypical Spitz and Non-Spitz Melanocytic Tumors (Melanocytomas): A Report From Children's Oncology Group
PURPOSE The purpose of this study was to develop recommendations for the diagnostic evaluation and surgical management of cutaneous melanoma (CM) and atypical Spitz tumors (AST) and non-Spitz melanocytic tumors (melanocytomas) in pediatric (age 0-10 years) and adolescent (age 11-18 years) patients. METHODS A Children's Oncology Group–led panel with external, multidisciplinary CM specialists convened to develop recommendations on the basis of available data and expertise. RESULTS Thirty-three experts from multiple specialties (cutaneous/medical/surgical oncology, dermatology, and dermatopathology) established recommendations with supporting data from 87 peer-reviewed publications. RECOMMENDATIONS (1) Excisional biopsies with 1-3 mm margins should be performed when feasible for clinically suspicious melanocytic neoplasms. (2) Definitive surgical treatment for CM, including wide local excision and sentinel lymph node biopsy (SLNB), should follow National Comprehensive Cancer Network Guidelines in the absence of data from pediatric-specific surgery trials and/or cohort studies. (3) Accurate classification of ASTs as benign or malignant is more likely with immunohistochemistry and next-generation sequencing. (4) It may not be possible to classify some ASTs as likely/definitively benign or malignant after clinicopathologic and/or molecular correlation, and these Spitz tumors of uncertain malignant potential should be excised with 5 mm margins. (5) ASTs favored to be benign should be excised with 1- to 3-mm margins if transected on biopsy. (6) Re-excision is not necessary if the AST does not extend to the biopsy margin(s) when complete/excisional biopsy was performed. (7) SLNB should not be performed for Spitz tumors unless a diagnosis of CM is favored on clinicopathologic evaluation. (8) Non-Spitz melanocytomas have a presumed increased risk for progression to CM and should be excised with 1- to 3-mm margins if transected on biopsy. (9) Re-excision of non-Spitz melanocytomas is not necessary if the lesion is completely excised on biopsy.
The association of nutritional and inflammatory status with cardiovascular and all-cause mortality risk among US patients with metabolic syndrome
First-Line Lenvatinib Plus Pembrolizumab Versus Chemotherapy for Advanced Endometrial Cancer: A Randomized, Open-Label, Phase III Trial
PURPOSE Lenvatinib plus pembrolizumab (len + pembro) significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in previously treated advanced or recurrent endometrial cancer (aEC) in the phase III Study 309/KEYNOTE-775. We report results from the phase III, randomized, open-label European Network of Gynaecological Oncological Trial-en9/LEAP-001 study (ClinicalTrials.gov identifier: NCT03884101 ) that evaluated len + pembro versus chemotherapy in first-line aEC. METHODS Patients with stage III to IV or recurrent, radiographically apparent EC and no previous chemotherapy or disease progression ≥6 months after neo/adjuvant platinum-based chemotherapy were randomly assigned 1:1 to lenvatinib 20 mg once daily plus pembrolizumab 200 mg once every 3 weeks or paclitaxel 175 mg/m 2 plus carboplatin AUC 6 mg/mL/min once every 3 weeks. Primary end points were PFS and OS, evaluated in the mismatch repair-proficient (pMMR) and all-comers populations. Noninferiority was assessed for OS at final analysis (FA) for len + pembro versus chemotherapy (multiplicity-adjusted, one-sided nominal alpha, .0159; null hypothesis–tested hazard ratio [HR], 1.1). RESULTS Eight hundred forty-two patients were randomly assigned (len + pembro, n = 420 [pMMR population, n = 320]; chemotherapy, n = 422 [pMMR population, n = 322]). At FA (data cutoff, October 2, 2023), median PFS (95% CI) in the pMMR population was 9.6 (8.2 to 11.9) versus 10.2 (8.4 to 10.5) months with len + pembro versus chemotherapy (hazard ratio [HR], 0.99 [95% CI, 0.82 to 1.21]) and among all-comers was 12.5 (10.3 to 15.1) versus 10.2 (8.4 to 10.4) months (HR, 0.91 [95% CI, 0.76 to 1.09]; descriptive analyses). Median OS (95% CI) in the pMMR population was 30.9 (25.4 to 37.7) versus 29.4 (26.2 to 35.4) months with len + pembro versus chemotherapy (HR, 1.02 [95% CI, 0.83 to 1.26]; noninferiority P = .246, not statistically significant per multiplicity control strategy) and among all-comers was 37.7 (32.2 to 43.6) versus 32.1 (27.2 to 35.7) months (HR, 0.93 [95% CI, 0.77 to 1.12]). Grade ≥3 treatment-related adverse events occurred in 331/420 (79%) versus 274/411 (67%) treated patients. CONCLUSION First-line len + pembro did not meet prespecified statistical criteria for PFS or OS versus chemotherapy in pMMR aEC.
Adolescent marriage, maternity, and limited access to education in 106 countries: Bayesian analysis of prevalence, trend, and prediction
Auditory efferent suppression during alternate auditory attention in schizophrenia patients with auditory hallucinations
CFD-based design of air wall water blocking for underground garage entrances and exits
In the increasingly perfect underground garage construction process, the underground garage entrance water blocking problem is getting more and more attention. This paper proposes a kind of air wall water-blocking device applied to underground garage. The device is installed on the side of the straight and curved paths at the entrances and exits of the spiral underground garage. It utilizes two fans to blow the water to the drain on the other side to achieve unobstructed access to stop the water. In this paper, CFD simulation is firstly carried out on the straight road of the spiral underground garage to verify the feasibility of the program. The accuracy of the simulation results was verified by building a straight road model and conducting experiments. After that, an equal-scale 3D model of the spiral underground garage was built. Orthogonal experiments on the effects of inlet water flow velocity, fan wind speed at the straight road and fan wind speed at the curved road on the water blocking effect were carried out by using CFD simulation. A preliminary range of water velocity of 2.250 m/min to 6.786 m/min was obtained experimentally, and this range of water velocity was used as an input parameter for the simulation. The results show that the speed of water flow at the entrance of the garage and the wind speed of the fan at the straight road have a greater effect on the water blocking effect than the wind speed of the fan at the curved road. When the wind speed of the fan at the straight road is 25m/s, proper adjustment of the wind speed of the fan at the curved road can realize a good water-blocking effect of the spiral underground garage entrance within the range of water flow rate of 2.250m/min ~ 6.786m/min. Therefore, in the practical application of using the air wall water blocking scheme to realize the underground garage entrance water blocking strategy is to give priority to improve the wind speed of the fan at the straight road to improve the effect of water blocking.
Protocol for human evaluation of generative artificial intelligence chatbots in clinical consultations
Background Generative artificial intelligence (GenAI) has the potential to revolutionise healthcare delivery. The nuances of real-life clinical practice and complex clinical environments demand a rigorous, evidence-based approach to ensure safe and effective deployment of AI. Methods We present a protocol for the systematic evaluation of large language models (LLMs) as GenAI chatbots within the context of clinical microbiology and infectious diseases clinical consultations. We aim to critically assess recommendations produced by four leading GenAI models, including Claude 2, Gemini Pro, GPT-4.0, and a GPT-4.0-based custom AI chatbot. Discussion A standardised, healthcare-specific, universal prompt template is developed to elicit clinically impactful AI responses. Generated responses will be graded by two panels of practicing clinicians, encompassing a wide spectrum of domain expertise in clinical microbiology and virology, as well as infectious diseases. Evaluations will be performed using a 5-point Likert scale across four clinical domains: factual consistency, comprehensiveness, coherence, and medical harmfulness. Our study will offer insights into the feasibility, limitations, and boundaries of GenAI in clinical consultations, providing guidance for future research and clinical implementation. Ethical guidelines and safety guardrails should be developed to uphold patient safety and clinical standards.
Hidden in plain sight: antisemitic content in QAnon subreddits
When is online content antisemitic? This matter is highly contested, except in the case of explicit language. Yet implicit antisemitic content and conspiracy narratives about Jews have been on the rise, especially on moderated platforms. This paper maps empirically the connections between explicit antisemitic content and these other forms of content, showing the language game at play in an online community identified as antisemitic and providing a relatively simple answer to the classification of content question. Using data from two QAnon subreddits, r/CBTS_Stream and r/greatawakening, we identify the co-occurrence of explicit and implicit antisemitic language posted to the subreddits. The language game involves an ingroup having specialized knowledge related to implicit language or dog whistles; the ingroup knows and uses the secret meaning of these terms as an insider’s code. Content network analysis and qualitative coding illustrate that QAnon taught this insider’s code by presenting the overt, antisemitic meanings of implicit terms and generalized narratives in posts that combined them with explicit language. While explicit language appeared rarely and was used by only a small proportion of users, more than a third of QAnon users employed implicit antisemitic language in their posts. This implicit language communicated antisemitic conspiracy narratives and antisemitic ideas more generally, to an audience “in the know” while also offering the user plausible deniability. Moreover, the implicit antisemitic terms circumvent platform censorship and provide an opportunity to leverage common ground around antisemitic conspiracy narratives with new users without the stigma of explicitly antisemitic content. The question of whether content is antisemitic may easily be answered by looking at a community’s posts that combine explicit and implicit antisemitic language. (272 words).
Triazination/IEDDA Cascade Modular Strategy Installing Pyridines/Pyrimidines onto Tyrosine Enables Peptide Screening and Optimization
Predictors of successful weaning from veno-arterial extracorporeal membrane oxygenation (V-A ECMO): A systematic review and meta-analysis
Background Venoarterial extracorporeal membrane oxygenation (V-A ECMO) use to support patients in cardiac failure is increasing. Despite this increased use, predicting successful weaning from ECMO can be challenging, no uniform guidelines on weaning exist. Therefore, we completed a systematic review to evaluate prognostic factors that predict successful weaning from V-A ECMO. Methods Following the PRIMSA guidelines, a systematic literature search of Medline, Embase, SCOPUS and CENTRAL identified original research studies of patients requiring V-A ECMO where weaning was attempted. Data was collected on demographic factors and weaning protocol, biomarkers, haemodynamic, echocardiographic factors for the successfully weaned (SW) and not successfully weaned (NSW) groups. Two investigators reviewed studies for relevance, extracted data, and assessed risk of bias using the ROBINS-I tool. The study was registered on the international prospective register of systematic reviews (PROSPERO ID# CRD42022366153). Results 1219 records were screened, of which 20 studies were deemed sufficient to be included in the statistical analysis based on pre-specified criteria. Factors associated with successful weaning were higher left ventricular ejection fraction (LVEF) (MD 9.0, 95% CI 4.1–13.8; p < 0.001) and left ventricular outflow tract velocity time integral (LVOT VTI) at time of weaning, (MD 1.35, 95% CI 0.28–2.40 lactate at admission (MD −3.2, 95% CI −4.8 to −1.5, p < 0.001), and CK-MB at admission (MD −4.11, 95%CI −6.6 to −1.6, p = 0.001). Critical appraisal demonstrated moderate-high risk of bias owing to confounding and low sample sizes. Conclusion In patients on V-A ECMO support being assessed for weaning multi-parametric assessment is required. Moderate-high heterogeneity and low sample sizes warrant higher-quality studies to help guide decisions to wean patients from V-A ECMO.