Kew (/kjuː/) is a district in the London Borough of Richmond upon Thames, 7.1 miles (11.4 km) west by south-west of Charing Cross; its population at the 2011 census was 11,436. Kew is the location of the Royal Botanic Gardens ("Kew Gardens"), now a World Heritage Site, which includes Kew Palace. Kew is also the home of important historical documents such as Domesday Book, which is held at The National Archives.Julius Caesar may have forded the Thames at Kew in 54 BC during the Gallic Wars. Successive Tudor, Stuart and Georgian monarchs maintained links with Kew. During the French Revolution, many refugees established themselves there and it was the home of several artists in the 18th and 19th centuries.Since 1965 Kew has incorporated the former area of North Sheen which includes St Philip and All Saints, the first barn church consecrated in England. It is now in a combined Church of England parish with St Luke's Church, Kew.Today, Kew is an expensive residential area because of its suburban hallmarks. Among these are sports-and-leisure open spaces, schools, transport links, architecture, restaurants, no high-rise buildings, modest road sizes, trees and gardens. Most of Kew developed in the late 19th century, following the arrival of the District line of the London Underground. Further development took place in the 1920s and 1930s when new houses were built on the market gardens of North Sheen and in the first decade of the 21st century when considerably more river-fronting flats and houses were constructed by the Thames on land formerly owned by Thames Water..
RATIONALE: The reported rate of P2X3 antagonist-associated dysgeusia varies widely in patients with refractory chronic cough (RCC). Camlipixant, a P2X3 antagonist in development for RCC in adults, has high selectivity (>1500×) for P2X3 over P2X2/3; thus, it is expected to improve tolerability by mitigating off-target P2X2/3-modulated dysgeusia. Other P2X3 antagonists of different magnitudes of selectivity have been investigated for RCC: sivopixant (262×), eliapixant (13×), gefapixant (1.5×), and filapixant (unknown). We hypothesized that clinically observed rates of dysgeusia are explained by selectivity, and all P2X3 antagonists would fall on a common potency-adjusted dose-response curve. METHODS: Clinical dysgeusia data from five P2X3 antagonists assessed in patients with RCC across nine clinical trials were collated by treatment arm. P2X3 antagonist dose was scaled by published P2X3 selectivity (or inferred based on eventual visual concordance for filapixant) and transformed using a log2 scale. The number of patients with dysgeusia was calculated from treatment sample size (intention-to-treat population); the proportion of patients with dysgeusia was reported with exact Clopper-Pearson 95% confidence intervals. All proportions were plotted against potency-scaled dose on a log2 scale; concordance between dysgeusia rates and potency was assessed using Loess regression. A linear mixed-effects logistic regression model was used to estimate the proportion of patients with dysgeusia with relative potency as the outcome measure of interest. RESULTS: Among 3,596 patients receiving P2X3 antagonists at a potency-adjusted dose of <8 mg, rates of dysgeusia were not numerically different from those receiving placebo. Thereafter, rates of dysgeusia increased in a log-linear manner (Figure), with the highest rates of dysgeusia (≤80%) reported for gefapixant. Camlipixant demonstrated dysgeusia rates comparable with placebo at all doses tested (≤200 mg). Using the same model, it was predicted that 2.8 times the highest dosage modelled (200 mg twice a day [BID]) of camlipixant would be needed to approach a similar dysgeusia rate to gefapixant (41% at the 45 mg BID dosage). CONCLUSIONS: In this model-based dose-response meta-analysis, the highly selective P2X3 antagonist camlipixant demonstrated placebo-like rates of dysgeusia over the clinical dose range modelled. After adjusting for relative selectivity, all P2X3 antagonists fell on the same tolerability dose-response curve, and the dosage of camlipixant currently under investigation in the CALM-1 and CALM-2 Phase 3 clinical trials (50 mg BID; NCT05599191, NCT05600777) was predicted to result in substantially lower rates of dysgeusia compared with a similar dosage of gefapixant.
Objective:Real-world data on the impact of mismatch repair (MMR) status in patients with advanced/recurrent endometrial cancer (A/R EC) are limited. England's National Disease Registration Service data were used to characterize outcomes by MMR status in patients with A/R EC potentially eligible for frontline immune-checkpoint inhibitor (ICI) treatment in addition to chemotherapy. Methods:Patients in this noninterventional, retrospective study were diagnosed with A/R EC between 2019 and 2021; received frontline chemotherapy; and met inclusion/exclusion criteria for the phase 3 RUBY trial (NCT03981796). Demographics, disease characteristics, and treatment patterns were reported. Overall survival (OS) and time-to-next-treatment (TTNT) were evaluated from initiation of frontline chemotherapy using Kaplan-Meier methodology. Results:Among 1452 ICI-eligible patients, 711 had MMR test results. Of these, 158 patients had MMR deficient (dMMR) tumors, and 547 had MMR proficient (MMRp) tumors. The dMMR cohort was younger (median, 64.4 years) with a larger percentage of endometrioid tumors (79.7%) than the MMRp (68.2 years and 40.8%, respectively) and untested cohorts (68.6 years and 41.2%, respectively). Median OS and TTNT were not reached in the dMMR cohort (median follow-up, 25.4 months); 34.6 (95% CI, 28.9-42.6) and 18.2 (95% CI, 15.3-22.1) months, respectively, in the MMRp cohort (median follow-up, 23.4 months); and 37.2 (95% CI, 27.4-45.9) and 18.2 (95% CI, 15.4-22.7) months, respectively, in the untested cohort (median follow-up, 24.3 months). Conclusion:In this real-world study, 51% of patients lacked MMR test results, reflecting the need for improved testing awareness. Among those tested, overall outcomes support the need for more effective frontline regimens to treat A/R EC.
To remedy the non-monophyly of Habenaria as demonstrated in several phylogenetic analyses, we propose here to expand the limits of the genus to include the species of Cooktownia, Diplomeris, Herminium, Pecteilis and Peristylus. Previously, Androcorys, Bhutanthera, Frigidorchis and Porolabium were synonymised with Herminium, and Bonatea, Centrostigma, Platycoryne and Roeperocharis with Habenaria. The proposed 16 new names and 69 combinations make Habenaria among the largest genera of Orchidaceae with roughly 1160 species.
Large language models (LLMs) are useful tools with the capacity for performing specific types of knowledge work at an effective scale. However, LLM deployments in high-risk and safety-critical domains pose unique challenges, notably the issue of “hallucinations”, where LLMs can generate fabricated information. This is particularly concerning in settings such as drug safety, where inaccuracies could lead to patient harm. To mitigate these risks, we have developed and demonstrated a proof of concept suite of guardrails specifically designed to mitigate certain types of hallucinations and errors for drug safety, with potential applicability to other medical safety-critical contexts. These guardrails include mechanisms to detect anomalous documents to prevent the ingestion of inappropriate data, identify incorrect drug names or adverse event terms, and convey uncertainty in generated content. We integrated these guardrails with an LLM fine-tuned for a text-to-text task, which involves converting both structured and unstructured data within adverse event reports into natural language. This method was applied to translate individual case safety reports, demonstrating effective application in a pharmacovigilance processing task. Our guardrail framework offers a set of tools with broad applicability across various domains, ensuring LLMs can be safely used in high-risk situations by eliminating the occurrence of key errors, including the generation of incorrect pharmacovigilance-related terms, thus adhering to stringent regulatory and quality standards in medical safety-critical environments.
OBJECTIVE:To evaluate secondary efficacy endpoints and safety for the ENGOT-OV16/NOVA (NCT01847274) trial of niraparib maintenance therapy after extended follow-up and vital-status-data retrieval. Previously reported analyses (data cutoff, October 1, 2020) indicated benefit of niraparib maintenance therapy beyond first progression, but overall survival (OS) analyses were limited by missing data. METHODS:Patients were randomized 2:1 to niraparib (300 mg once daily) or placebo. A vital status check was extended to retrieve last-known-alive status for patients with missing survival data. Prespecified secondary efficacy outcomes (OS, chemotherapy-free interval [CFI], time to first subsequent therapy [TFST], PFS2, time to second subsequent therapy [TSST]) and safety are reported based on the extended data cutoff (March 31, 2021). RESULTS:Survival status was available for 97.6% (540/553) of randomized patients (germline BRCA [gBRCA]-mutated, 203; non-gBRCA-mutated, 350). Median OS with niraparib and placebo was 40.9 and 38.1 months, respectively, in the gBRCA-mutated cohort (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.61-1.20) and 31.0 and 34.8 months, respectively, in the non-gBRCA-mutated cohort (HR, 1.06; 95% CI, 0.81-1.37). Medians for CFI, TFST, PFS2, and TSST numerically favored niraparib in both cohorts. No new safety signals were detected. CONCLUSIONS:OS did not significantly differ between treatment arms. Prespecified secondary efficacy endpoints numerically favored niraparib. Long-term safety remained consistent with the established niraparib safety profile. Taken together with the significant improvements in PFS observed in the primary analysis, these data support a favorable overall benefit-risk profile for niraparib in the recurrent OC maintenance setting.
